Next Article in Journal
Naringin and Naringenin Polyphenols in Neurological Diseases: Understandings from a Therapeutic Viewpoint
Previous Article in Journal
Persistence of Symptoms 15 Months since COVID-19 Diagnosis: Prevalence, Risk Factors and Residual Work Ability
Previous Article in Special Issue
MiR-371a-5p Positively Associates with Hepatocellular Carcinoma Malignancy but Sensitizes Cancer Cells to Oxaliplatin by Suppressing BECN1-Dependent Autophagy
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Life
Volume 13
Issue 1
10.3390/life13010098
life-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Redox Regulation of Autophagy in Cancer: Mechanism, Prevention and Therapy

by
Jingqiu He
1,†,
Lixia Dong
1,†,
Li Luo
2,3,* and
Kui Wang
1,*
1
West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China
2
Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
3
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Life 2023, 13(1), 98; https://doi.org/10.3390/life13010098
Submission received: 29 November 2022 / Revised: 18 December 2022 / Accepted: 22 December 2022 / Published: 29 December 2022
(This article belongs to the Special Issue The Interplay between Autophagy and ROS in Cancer)
Browse Figures
Versions Notes

Abstract

:
Reactive oxygen species (ROS), products of normal cellular metabolism, play an important role in signal transduction. Autophagy is an intracellular degradation process in response to various stress conditions, such as nutritional deprivation, organelle damage and accumulation of abnormal proteins. ROS and autophagy both exhibit double-edged sword roles in the occurrence and development of cancer. Studies have shown that oxidative stress, as the converging point of these stimuli, is involved in the mechanical regulation of autophagy process. The regulation of ROS on autophagy can be roughly divided into indirect and direct methods. The indirect regulation of autophagy by ROS includes post-transcriptional and transcriptional modulation. ROS-mediated post-transcriptional regulation of autophagy includes the post-translational modifications and protein interactions of AMPK, Beclin 1, PI3K and other molecules, while transcriptional regulation mainly focuses on p62/Keap1/Nrf2 pathway. Notably, ROS can directly oxidize key autophagy proteins, such as ATG4 and p62, leading to the inhibition of autophagy pathway. In this review, we will elaborate the molecular mechanisms of redox regulation of autophagy in cancer, and discuss ROS- and autophagy-based therapeutic strategies for cancer treatment.

1. Introduction

Redox (reduction and oxidation) reaction refers to a type of reaction in which electron transfer occurs. During the cellular redox process, the most important active molecules produced are reactive oxygen species (ROS) and reactive nitrogen species (RNS) [1]. Reactive oxygen species (ROS), as byproduct of aerobic metabolism, are highly active ions and molecules derived from molecular oxygen (O2), which include the superoxide anion (O2–), hydrogen peroxide (H2O2) and hydroxyl radicals (•OH) [2]. While RNS consist of nitric oxide (NO), nitrogen dioxide radical (NO2), nitrite (NO2−), nitrate (NO3−) and peroxynitrite (OONO−) [3,4]. Both ROS and RNS are potent oxidants that can cause intracellular oxidative stress. Initially, elevated ROS levels were thought to be harmful to cells, causing damage to intracellular components and even cell death [5]. However, in-depth studies have shown that the role of ROS in cells is complex and contradictory under both physiological and pathological conditions. ROS maintain redox homeostasis in cells and participate in the regulation of multiple signaling pathways [1]. ROS are associated with cancer, diabetes, cardiopulmonary diseases and many other diseases.
Autophagy is a cellular lysosomal-dependent degradation mechanism that eliminates damaged organelles, misfolded proteins and pathogens to maintain cellular homeostasis [6]. In the face of various stress conditions such as oxidative stress, nutrition restriction, and growth factor deficiency [7], a double-membraned autophagosome encapsulates the cytoplasmic components and delivers them to the lysosomes for degradation and recycling. This degradation and recovery mechanism of autophagy will protect cells from the accumulation of damaged proteins, prevent the attack of microorganisms, and maintain the nutritional supply [8]. Therefore, a basal low level of autophagy is essential for cell survival and homeostasis [9]. A growing number of studies have shown that autophagy is associated with the pathogenesis of various diseases, including cancer. Regulating the activity of autophagy may impact cancer progression, and targeting autophagy in cancer cells has gradually proved to be an effective strategy for cancer treatment [10].
Various cancer cells often exhibit elevated intracellular ROS levels, mainly due to dysregulated metabolism, mitochondrial dysfunction, and oncogenic mutations, etc. [11]. Studies have shown that ROS accumulation plays a variety of roles in cancer. Emerging reports have also confirmed that ROS can directly oxidize and modify autophagy-related proteins, thus regulating autophagy process. In this review, we will summarize the role of ROS as signaling molecules in regulating autophagy process in the survival or death of cancer cells in different settings. We then discuss the potential of molecules or pathways involved in the redox regulation of autophagy as future therapeutic targets for cancer treatment.

2. ROS and Cancer

The prominent sources of O2– are mitochondrial respiration and membrane-bound NADPH oxidase (NOX) complex [12]. Electron leakage from the mitochondrial electron transport chain (ETC) leads to one-electron reduction of O2 and subsequent generation of O2– [13]. NOXs are membrane location proteins that catalyze the transfer of electrons from NADPH to O2 to form O2– [14]. Under the catalysis of superoxide dismutases (SODs), O2– can be quickly converted into H2O2, H2O2 can then be catalyzed by metal catalyst through the Fenton chemical reaction to generate hydroxyl radicals (•OH) [15]. Beyond that, the accumulation of ROS may lead to the production of RNS [16]. RNS molecules, which are primarily derived from nitric oxide reaction, also participate in various cellular signaling pathways to regulate biological events [17].
To counteract the damage of ROS accumulation, cells are equipped with an elaborate antioxidant defense system [18]. The antioxidant defense system mainly comprises nonenzymatic and enzymatic antioxidants to cope with oxidative stress. In general, nonenzymatic antioxidants are usually refer to glutathione (GSH), flavonoids, vitamin A and other small molecules [19]. Among them, GSH is one of the most important antioxidant molecules. After receiving the single electron of ROS or RNS, two GSH molecules generate oxidized dimer (GSSG). GSSG can be regenerated into GSH under the catalysis of glutathione reductase (GR) to maintain intracellular redox homeostasis [20]. Cells also have enzymatic antioxidants, including SODs, catalases (CATs), glutathione peroxidases (GPXs), peroxiredoxins (PRXs), thioredoxins (Trxs) and paraoxonase-2 (PON2), that participate in cytoprotective and detoxification processes [21]. As mentioned above, SODs convert O2– to H2O2, which in turn is catalyzed to produce water by CATs with the participation of GPXs and PRXs [22]. PON2 reduces the release of O2– from the inner mitochondrial membrane, thus protecting cells from oxidative stress [23,24]. Studies have proved that PON2 is overexpressed in some solid tumors, and it has been proposed as a therapeutic target for several malignant tumors such as glioblastoma multiforme, bladder cancer and melanoma [25,26,27,28]. The source and conversion of active oxygen are shown in Figure 1.
Intracellular redox state is related to many pathological states, among which cancer is a hot research field. Previous studies observed that the accumulation of ROS can exhibit a variety of contradictory biological effects and participate in the process of cell growth, cell death and metastasis of cancer cells. The specific outcome depends on the genetic background of tumor cells, as well as the distributions, concentrations, and durations of ROS. For example, ROS can promote rapid tumor reproduction by directly oxidizing the cysteine residues of metabolic enzymes involved in glycolysis, fatty acid metabolism and energy homeostasis of cancer cells [29]. In addition, ROS can act as the second messenger in cancer cells, leading to the activation of several carcinogenic pathways or inactivation of cancer inhibition pathways [30]. For example, ROS promote the survival of tumor cells by activating mitogen activated-protein kinase (MAPK)/extracellular-regulated kinase 1/2 (ERK1/2) [31], phosphoinositide-3-kinase (PI3K)/Akt [32] and nuclear factor-κB (NF-κB) pathways [33], inactivating the tumor-suppressor gene p53 [34] and stabilizing the transcriptional factor Nrf2 [35]. ROS can also affect the tumor microenvironment (TME). A number of studies have shown that ROS could promote the conversion of normal fibroblasts into cancer-associated fibroblasts (CAFs) in tumors to augment tumorigenesis. Moreover, ROS could inhibit the function of tumor-infiltrating T-cells to form an immunosuppressive microenvironment [36]. In addition to these tumor-promoting roles, the excessive production of ROS has toxic effects on tumor cells, such as inducing cell cycle arrest, DNA damage, apoptosis and aging [19,37,38]. In addition, ROS are also involved in the regulation of tumor metastasis, which is also contradictory and complex. It has been reported that targeted removal of superoxide by mitoTEMPO (a specific scavenger of mitochondrial superoxide) effectively blocked the lung metastasis of breast cancers in mice [39]. However, studies have also shown that the antioxidant NAPDH-generating enzymes promoted the distant metastasis of human melanoma cells [40].

3. Autophagy and Cancer

The autophagy process firstly originates from the formation of isolation membranes (IM), followed by the recruitment of the core proteins of autophagy (ATGs) to phagophore assembly site (PAS) for assembly [41,42]. Unc-51 like autophagy activating kinase 1 (ULK1) complex, which is activated by inactivation of the mammalian target of rapamycin complex 1 (mTORC1), regulates the composition and activity of class Ⅲ PI3K complex by phosphorylating its components, Beclin 1 and autophagy/beclin-1 regulator 1 (Ambra1) [43]. The activation of the class Ⅲ PI3K complex leads to sequential steps, including recruitment of ATG proteins to PAS for membrane bending, phosphorylation of the lipid head group of phosphatidylinositol to produce phosphatydilinositol-3-phosphate (PI(3)P), and guidance of autophagosome maturation [44]. The elongation of autophagosomes requires two ubiquitin-like conjugation systems: the ATG12-ATG5 and the LC3/ATG8-phosphatidylethanolamine (PE) system. In the first system, as a ubiquitin-like protein, ATG12 firstly conjugates with ATG5 under the action of ATG7 (E1-like enzyme) and ATG10 (E2-like enzyme) [45]. The ATG12-ATG5 conjugate then combines with ATG16L1 to form ATG12–ATG5- ATG16L1 complex, which serves as an E3-like enzyme to couple LC3/ATG8 to PE [46]. Concomitantly, under sequential action of the protease ATG4, the E1-like enzyme ATG7, E2-like enzyme ATG3, and E3-like ligase ATG12-ATG5-ATG16L1 complex, the cytosolic LC3 (LC3-I) is converted to LC3-PE conjugate (LC3-II) [47,48]. Additionally, autophagosome-associated LC3 proteins remain on the membrane of autophagosomes until their fusion with lysosomes [49]. After combining with PE, LC3/ATG8 can recruit a variety of proteins through direct interactions to promote the supplement and transportation of cargoes, as well as lysosomal fusion [50]. Once the membrane of autophagosomes has been sealed, the autophagosomes will undergo a maturation process, during which the autophagosomes are delivered to and fused with the lysosomes [51,52]. Finally, under the action of lysosomal hydrolase and acidic environment, the intracellular contents of autophagosomes are degraded, while the membrane components of autophagosomes are circulated by autophagic lysosome reform (ALR) for cell reuse, so as to realize the metabolic needs and maintenance of intracellular homeostasis [53]. The process of autophagy is also shown in detail in Figure 2.
Autophagy can act as either tumor suppressor or tumor promoter according to the stage of cancer. There are two main types of evidence for autophagy as tumor suppressor. On the one hand, the absence of certain autophagy genes can lead to tumorigenesis. For example, the autophagy gene Beclin 1 (ATG6) exhibits mono-allelic deficiency in 40–75% of sporadic human breast cancers and ovarian cancers, indicating that Beclin 1 is a tumor-suppressor gene [54]. On the other hand, activation of certain oncogenes or inactivation of tumor-suppressor genes will inhibit autophagy. For instance, oncogenic proteins Bcl-2 and Bcl-XL can inhibit autophagy by interacting with Beclin 1 [55]. In addition, overexpression of AKT in a variety of tumors can activate mTOR, leading to blockage of autophagy process. Thus, the combination of pro-autophagic drugs with inhibitors of mTOR, PI3K, or AKT, shows potent anticancer effect [56]. In contrast to its role in constraining tumor initiation, a plethora of studies have shown that autophagy promotes tumor cell survival in advanced cancer. Under the condition of metabolic stress, autophagy can provide energy and essential building blocks for rapidly proliferating tumor cells by circulating intracellular substances, enabling them to thrive in austere microenvironment [57,58]. It has also been shown that autophagy is associated with drug resistance in numerous types of tumor cells. Some residual or metastatic tumor cells can tolerate cytotoxic stress through activating autophagy to become resistance to anticancer drugs [59]. Therefore, therapeutic schemes targeting autophagy inhibition, such as knockdown of LC3 in drug-resistant cells, can sensitize tumor cells to anticancer drugs [60]. Taken together, the autophagy-related pathways are promising targets for cancer treatment, and it is important to fully and deeply understand the complex role of autophagy in cancer.

4. Indirect Redox Regulation of Autophagy in Cancer

As mentioned above, both ROS and autophagy are involved in the progression and treatment response of cancer. How ROS regulate autophagy in cancer cells has also become a hot research topic. ROS can indirectly or directly regulate autophagy and thus participate in the development of cancer (Figure 3). Accumulating evidence indicates that reactive cysteines in proteins are molecular switches for transduction of redox signals. The active thiol side chain on cysteine residues of a target protein can be oxidized by ROS to form a sulfenic acid (SOH), which may be further oxidized to form an intramolecular disulfide bond or a S-glutathionylated (SSG) intermediate with glutathione (GSH) [61,62]. These oxidative modifications are reversible, and the oxidation products can be reduced to thiol through the Trx/Trx reductase (or Grx/Grx reductase) with NADPH providing reducing equivalents [63]. Oxidative modifications of reactive cysteines can cause conformational changes of target proteins to transduce redox signals by affecting enzyme activity, protein interaction and further posttranslational modification [29].

4.1. Post-Transcriptional Regulation

4.1.1. mTOR Pathway

mTOR is considered to be a core protein in the regulation of autophagy. A classic pathway involved is AMPK/TSC1/2/mTOR signaling axis. In the stress conditions, the increased [AMP]/[ATP] ratio leads to the activation of AMP-activated protein kinase (AMPK), which phosphorylates and activates TSC1/2 protein complex, and sequentially inactivates mTOR [64]. mTOR complex has two different forms—mTORC1 and mTORC2 [65]. mTORC1 is a main regulator of autophagy, and its activation inhibits the initiation of autophagy by phosphorylating ULK1/2 (Ser637 and Ser757) and ATG13 (Ser258) proteins [66]. In addition, PI3K/AKT signaling is also involved in autophagy initiation through regulating mTOR. Extracellular signals such as cytokines and growth factors can be transduced to class I phosphatidylinositol 3-kinase complex (PI3K) through G protein-coupled receptors (GPCRs) and tyrosine kinases (RTKs), and the activated PI3K catalyzes the production of phophatidylinositol-3,4,5-triphosphate (PIP3), thus stimulating AKT and other downstream signaling molecules. Activated AKT promotes the activity of mTORC1 by inhibiting TSC1/TSC2, thereby inhibiting autophagy stimulation [67,68]. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) can antagonize PI3K signal by dephosphorylating PIP3 [69]. It has been reported that the components of the upstream and downstream signaling of mTOR pathway are often changed to promote tumor progression in various types of cancers, such as amplification of PI3K, loss of PTEN function and overexpression of AKT [70].
The AMPK can act as an energy sensor to monitor the intracellular energy level [71]. Studies have shown that increased levels of intracellular ROS can activate AMPK for the maintenance of redox homeostasis. For example, Wu et al. found that in response to H2O2 treatment, AMPK was phosphorylated and activated to induce autophagy to counteract oxidative stress, thus enabling cell survival [72,73]. The activation of AMPK by H2O2 might be due to direct S-glutathionylation of Cys299 and Cys304 [74]. In tumor cells, activated AMPK is thought to maintain redox homeostasis, at least in part, by regulating the initiation of autophagy, thus being closely related to tumor progression [75].
AKT was originally found as an oncogene involved in the regulation of the survival, proliferation, and death pathways of tumor cells [76]. PTEN, a phosphatase that opposes forward PI3K signaling, can positively regulate autophagy and exert anti-tumor effect by inhibiting AKT activation [77]. Leslie et al. demonstrated that H2O2 could oxidize and deactivate PTEN in glioblastoma cells. Inactivation of PTEN caused an increased intracellular PIP3 level, which in turn led to the activation of the downstream AKT [78]. Further study showed that Cys124 of PTEN specifically formed disulfide bond with Cys71 in response to H2O2 treatment [79]. In addition, some studies showed that ROS could directly regulate the activity of AKT. Under oxidative stress, AKT formed intramolecular disulfide bonds between Cys297 and Cys311, leading to its dephosphorylation and inactivation by binding to protein phosphatase PP2A [80]. However, whether AKT-regulated autophagy promotes tumor survival by maintaining redox homeostasis or plays a cytotoxic role by inducing tumor cell death remains to be explored.
Walker’s group reported that ROS could oxidize and activate ataxia-telangiectasia mutated (ATM) to repress the downstream TSC2-mTOR signaling pathway, thus initiating autophagy [81]. Different from the classical pathway for ATM activation via DNA double-strand breaks in the nucleus, it has been reported that H2O2 treatment could directly oxidize ATM through forming a disulfide-cross-linked dimer at Cys2991, leading to ATM activation [82]. It has been reported that ATM could induce intestinal cell death of Caenorhabditis elegans by stimulating autophagy in response to oxidative stress [83]. Walker’s group later demonstrated that ROS may also be involved in the cargo identification of autophagy [84]. The peroxisome import receptor PEX5 could bind and re-localize ATM to the peroxisomes. ROS-induced ATM activation promotes the mono-ubiquitination of Lys209 by phosphorylating the Ser141 site of PEX5. The autophagy adapter p62 then recognized the ubiquitinated PEX5 to direct the autophagosomes to engulf the peroxisomes [85].
In addition to ROS, it has been demonstrated that nitric oxide (NO) could S-nitrosylate IKKβ and reduce its phosphorylation, thus preventing AMPK phosphorylation and impairing autophagy initiation [86]. Interestingly, different from the traditional viewpoint of RNS as an autophagy inhibitor, some studies have pointed out that NO could induce autophagy. In breast cancer cells, nitrogen stress caused rapid activation of the ATM damage-response pathway and downstream LKB1, which ultimately inhibited AMPK/TSC1/2/mTOR pathway to induce autophagy [87]. Therefore, cancer cells are particularly sensitive to nitrogen stress, and nitrosative stress-induced autophagy might be a promising therapeutic target for cancer treatment.
The redox regulation of the mTOR signaling pathway is not limited to the upstream molecules. Recent studies have shown that ROS could directly oxidize mTOR. Oka et al. found that an intermolecular disulfide bond formed at Cys1483 of mTOR in cultured cardiomyocytes following H2O2 treatment, resulting in the mTOR inactivation and the inhibition of downstream signaling [88]. Although the oxidation of mTOR has not been reported in tumor cells, given the important role of ROS, mTOR signaling and autophagy in tumor progression, it is reasonable to presume that ROS might be involved in tumor progression by directly oxidizing mTOR to regulate autophagy.
In conclusion, these observations suggest that the mTOR signaling pathway is a key regulatory step in ROS-induced autophagy, but the exact molecular mechanism between ROS-induced autophagy and mTOR signaling in cancer remains to be further investigated.
Life 13 00098 g003 550
Figure 3. The redox regulation of autophagy. (A) mTOR is a core protein countering autophagy initiation. ROS can oxidize and modify AMPK, PTEN, AKT, ATM and other molecules to regulate their activities, and transmit the signal through mTOR to affect autophagy initiation. Beclin 1 usually binds to Bcl-2 to inhibition autophagy initiation, while the oxidative modification of upstream regulatory factors such as JNK1, ASK1 and CAV1 can destroy this interaction to stimulate autophagy. (B) In addition, ROS have been demonstrated to affect the autophagy process by regulating the activities and interactions of related transcription factors, including Nrf2, TFEB and HIF-1, resulting in the increased transcription of autophagy-related genes. (C) Notably, there is a few evidence for the direct regulation of autophagy by ROS. Currently, it is known that ROS can directly oxidize and modify ATG4 and p62 to participate in the autophagy expansion and cargo recognition processes, respectively.
Figure 3. The redox regulation of autophagy. (A) mTOR is a core protein countering autophagy initiation. ROS can oxidize and modify AMPK, PTEN, AKT, ATM and other molecules to regulate their activities, and transmit the signal through mTOR to affect autophagy initiation. Beclin 1 usually binds to Bcl-2 to inhibition autophagy initiation, while the oxidative modification of upstream regulatory factors such as JNK1, ASK1 and CAV1 can destroy this interaction to stimulate autophagy. (B) In addition, ROS have been demonstrated to affect the autophagy process by regulating the activities and interactions of related transcription factors, including Nrf2, TFEB and HIF-1, resulting in the increased transcription of autophagy-related genes. (C) Notably, there is a few evidence for the direct regulation of autophagy by ROS. Currently, it is known that ROS can directly oxidize and modify ATG4 and p62 to participate in the autophagy expansion and cargo recognition processes, respectively.
Life 13 00098 g003

4.1.2. Beclin 1

Beclin 1 is an indispensable protein in the process of autophagy, and Beclin 1 gene is also the first discovered gene to link autophagy with human tumors [89]. The Bcl-2 family of proteins, Bcl-2, Bcl-xL and Mcl-1, which are anti-apoptotic proteins, can bind to the Bcl-2 homology 3 (BH3) domain of Beclin 1 to exert a rheostat effect for autophagy [90]. Under normal conditions, Beclin 1 binds to Bcl-2. When separating from Bcl-2, Beclin 1 can form PI3KC3 complex with Vps15, Vps34 (also called type III PI3K) and other proteins like Ambra1, to regulate the initiation of autophagy [42]. Studies have shown the downregulation of Beclin 1 and upregulation of Bcl-2 in many types of cancers, both were closely related to poor prognosis [91,92]. It has been reported that Bcl-2 antagonized the autophagy pathway, subverted the internal protein quality and genome stability and promoted the growth of breast cancer cells, indicating that Beclin 1 and Bcl-2 can be served as attractive targets for cancer therapy [93].
As mentioned above, the dissociation of Bcl-2/Beclin 1 complex is essential for the initiation of autophagy, which is regulated by key kinases. For example, nutritional stress-activated c-Jun N-terminal protein kinase 1 (JNK1, also known as mitogen-activated protein kinase 8, MAPK8), promoted multisite phosphorylation of Bcl-2, leading to the dissociation of Bcl-2 from Beclin 1, thereby inducing autophagy [94]. The typical MAPK pathway consists of three sequentially activated MAPK family members, including MAPK kinase kinase (MAPKKK), MAPK kinase (MAPKK) and MAPK [95]. ROS are considered as a potent inducer for the activation of the MAPK family members. It has been reported that ROS inactivated MAPK phosphatase 3 (MKP-3) by oxidizing Cys293 to sulfenic acid, and then continuously activated JNK1 [96]. Further studies have shown that ROS-mediated JNK activation could induce autophagy by upregulating ATG5 and ATG7, which is crucial for oncogenic K-Ras-induced malignant cell transformation [97]. Inhibition of oxidative stress with antioxidants, or ATG5 or ATG7 knockdown using shRNA obviously inhibited autophagy and prevent malignant transformation [98]. ROS could also activate JNK1 by oxidizing ASK1 (a ubiquitously expressed MAPKKK). Thioredoxin is an internal inhibitor of ASK1, and its redox state determines the activity of ASK1. ROS can cause thioredoxin to form an intramolecular disulfide between Cys32 and Cys35 residues, leading to the dissociation of oxidized thioredoxin from ASK1 and the subsequent activation of ASK1 [99,100]. Similarly, researchers also found that ROS could oxidize glutaredoxin, thus promoting its dissociation from ASK1 and causing JNK1 activation [101]. It has been reported that endogenous nitric oxide could cause S-nitrosylation at Cys116 of JNK1, which is proved to be a critical cysteine residue for the thiol-redox regulation of JNK1, resulting in JNK1 inactivation [102]. Through inhibiting JNK1-mediated Bcl-2 phosphorylation, NO increases the interaction of Bcl-2 with Beclin 1 to inhibit autophagy initiation [86].
Some other regulatory factors have also been reported to be sensitive to redox state and regulate Beclin 1-mediated autophagy. For example, H2O2 treatment promoted the phosphorylation of CAV1 (Caveolin-1, an integral membrane protein) at Tyr14. The phosphorylated CAV1 then interacted with Beclin 1-Vps34 complex through its scaffolding domain to promote the formation of autophagosomes. When the phosphorylation of CAV1 was reduced by PTEN1, or CAV1 was knocked out, autophagy flux was decreased [103]. However, in contradiction with above report, it has been proved that ROS could inhibit autophagy initiation through TRPM2-Ca2+-CAMK2-Beclin 1 cascade. In detail, ROS triggered TRPM2-dependent Ca2+ influx, mediated the oxidation of two adjacent methionine residues (Met281 and Met282) in CAMK2, and then phosphorylated Beclin 1 at Ser295. The phosphorylation of Beclin 1 enhanced its interaction with Bcl-2, leading to the inhibition of autophagy at early stage [104].
Notably, the regulation of autophagy by ROS can also be achieved by regulating Vps34 and its interaction with Beclin 1. Eisenberg-Lerner et al. demonstrated that under oxidative stress, PKD was phosphorylated and consequently activated by DAPK (death-associated protein kinase) [105]. Activated PKD then phosphorylated and activated Vps34 leading to the production of PI3Pand formation of autophagosome. Another example is cannabidiol, an antineoplastic agent, promoted ROS generation and induced cell death of breast cancer cells. In addition, cannabidiol promoted the dissociation of Beclin 1 and Bcl-2, and enhanced the interaction of Beclin 1 with Vps34 to induce autophagy. Scavenging of ROS led to the blockage of cannabidiol-induced autophagy, suggesting that cannabidiol regulate autophagy through inducing oxidative stress [106]. Moreover, cannabidiol-induced autophagy did not maintain homeostasis in breast cancer cells, but rather promoted cell death and inhibited tumor development, which once again suggest the double-edged sword effect of autophagy in tumor cells.

4.2. Transcriptional Regulation

4.2.1. p62/Keap1/Nrf2

In addition to the effects of ROS on the oxidative modification and interaction of the upstream regulatory molecules in the autophagy process, ROS can also regulate autophagy by affecting gene transcription. Nrf2, a key transcription factor in the antioxidant defense system, activates the transcription of SOD, catalase, GR, heme oxygenase (HO-1) and other antioxidant enzymes to protect cells from oxidative stress [107]. Under unstressed conditions, Nrf2 interacts with the Kelch-like ECH-associated protein 1 (Keap1), which mediates Nrf2 ubiquitination and promotes the proteasomal degradation of Nrf2 [108]. In response to oxidative stress, Nrf2 dissociates from Keap1 and subsequently enters the nucleus [35]. Nuclear Nrf2 specifically binds to the antioxidant response element (ARE) located in the promoter of the autophagy adaptor sequestosome 1 (p62/SQSTM1), and then promotes the transcription of p62 [109]. Phosphorylation of p62 increases the binding affinity for Keap1 and competitively separates Nrf2 from Keap1, thereby forming a positive feedback loop [110,111].
Elevated p62 levels are essential for tumorigenesis. Mathew et al. found that autophagy-defective cells resulted in the accumulation of p62 and promoted tumorigenesis [112]. The research on autophagy-defective mouse models also provided strong evidence for this viewpoint. For example, accumulation of p62 and Keap1 protein aggregates and sustained activation of Nrf2 were observed in liver-specific autophagy-deficient mice and demonstrated to be associated with the hepatocarcinogenesis [113]. In addition to tumorigenesis, the upregulation of p62 was also associated with cancer progression and therapeutic resistance [114]. It should be mentioned that a variety of natural and synthetic compounds, such as γ-tocopherol (γ-TmT) and sulforaphane (SFN), could elevate the expression of Nrf2 to protect cells from oxidative stress, thereby significantly reducing the incidence of prostate cancer in transgenic adenocarcinoma of mouse prostate (TRAMP) mice [115]. Taken together, drugs targeting the p62/Keap1/Nrf2 signaling pathway, such as p62 inhibitors and Nrf2 modulators have potential to become new strategies for tumor treatment.

4.2.2. TFEB

Transcription factor EB (TFEB) is an important transcription factor involved in lysosomal biogenesis and autophagy [116]. TFEB can interact with Rag GTPases and be recruited to lysosomes in an amino acid-dependent manner [117]. Later, TFEB is phosphorylated by mTOR at Ser211 and sequestered in the cytosol through binding with 14-3-3 proteins [85]. Under stress, inactivation of mTOR results in dephosphorylation and nuclear translocation of TFEB, leading to the transcription of genes required for lysosomal biogenesis and autophagy induction [118].
Recently, Wang et al. revealed a new mechanism that TFEB can be directly oxidized and activated by ROS, thus activating autophagy [119]. They found ROS directly oxidized TFEB at Cys212, thus abolishing the interaction between Rag GTPases and TFEB and inducing rapid nuclear translocation of TFEB independent of mTOR inhibition. It was found that H2O2 treatment increased the expression of genes involved in autophagy-lysosome system, indicating that the activation of TFEB was required for ROS-driven autophagy. Dysfunction in autophagy-lysosome system is closely associated with many human diseases, and therapeutic strategies targeting this process have also been developed. For example, salidroside, an active ingredient separated from the traditional Chinese herbal medicine Rhodiola rosea, promoted the nuclear translocation of TFEB by inducing ROS accumulation, leading to the induction of autophagy and apoptosis in human chondrosarcoma cells [120].

4.2.3. HIF-1

Hypoxia is often present in the tumor area due to excessive proliferation, high oxygen consumption, and limited extent of tumor angiogenesis [121]. Hypoxia inducible factor-1 (HIF-1) is a key transcription factor for cancer cells to adapt to the hypoxic environment, and has been proven to be an important cancer drug target [122]. This transcription factor has oxygen-dependent instability, which degrades rapidly under normoxic conditions, but can exist stably under anoxic conditions or generation of mitochondrial ROS [123]. HIF-1 can drive the transcription of hundreds of genes involved in angiogenesis, glucose metabolism, migration and invasion in tumor cells [124]. Kobayashi et al. demonstrated that prolonged hypoxia increased the levels of ROS, inducing the expression of redox factor-1 (Ref-1) to activate HIF-1 [125]. Some studies suggest that the mechanisms for the occurrence of hypoxia in tumor is that the production of ROS can cause vascular endothelial damage [126]. Hypoxia could rapidly induce the survival response of autophagy through HIF-1. In detail, HIF-1 induced the transcription of pro-apoptotic genes BNIP3 and NIX to compete for Beclin 1 binding with Bcl-2, thus releasing Beclin 1 to induce autophagy [127]. Of interest, NO has been reported to promote the stabilization and transcriptional activity of HIF-1 by S-nitrosation of Cys800 [128]. Given the multiple roles of HIF-1 in autophagy and tumor progression, inhibitors of HIF-1 and its downstream pathways have also become promising targets for cancer treatment.

5. Direct Redox Regulation of Autophagy in Cancer

5.1. ATG4

Although there is a large amount of data supporting the viewpoint of redox regulation of autophagy, the evidence for direct regulation of autophagy-related proteins by redox signaling remains limited. ATG4 is the first ATG family protein identified to be directly oxidized by ROS. There are four different ATG4 homologs expressed in human: ATG4A, ATG4B, ATG4C and ATG4D, among which ATG4B is crucial for the autophagic process [129]. ATG4 plays a key role in the regulation of the ATG8/ LC3 lipid conjugation system. First, the cysteine protease ATG4 cleaves pro-LC3 to expose a glycine residue (Gly120) near the C-terminus to form conjugates with PE by ubiquitin-like systems [130]. Second, after autophagosome closure, membrane-localized LC3-II is delipidated by ATG4 at the bond between Gly120 residue and PE to recycle LC3-I [131].
Given the dual role of ATG4, its activity should be tightly regulated. To investigate this regulatory mechanism, Scherz-Shouval and colleagues found that recombinant HsAtg4A was active only in the presence of the reductant DTT, suggesting that the activity of ATG4 might be regulated by redox potential [132]. The authors went on to find that ROS, specifically H2O2, could directly oxidize and regulate ATG4 in nutrient starvation-induced autophagy [133]. They specified Cys81 of ATG4A and Cys78 of ATG4B as critical sites for this regulation. Mutation of these two sites to serine significantly prevented LC3 lipidation and autophagosome formation. Taken together, starvation-induced oxidative signals caused inactivation of ATG4 at the site of autophagosome formation, thus promoting lipidation of ATG8 to facilitate autophagosome formation. However, since Cys81 is not conserved, the molecular mechanism is distinct in different species. It has been reported that redox regulation of ATG4 in yeast cells was mediated by the formation of a single disulfide bond between Cys338 and Cys394 [134]. Similarly, Li et al. recently found that the mechanism of ATG4B inactivation upon exposure to oxidants in HEK293 and Hela cells was the formation of intermolecular disulfide bond between Cys292 and Cys361 [135]. Mutation of both Cys292 and Cys361 reduced the redox sensitivity of ATG4B and increased autophagic flux. In addition to ROS, it has been observed that high glucose level could induce RNS accumulation, which mediated the impaired synthesis of autophagosomes to inhibit autophagic flux. The activity of ATG4B was compromised by RNA-mediated S-nitrosation at Cys189 and Cys292. The impaired autophagy mediated by ATG4B S-nitrosation led to neurotoxicity in response to high glucose level [136].
Interestingly, Frudd et al. reported a different thiol-dependent process for the negative regulation of autophagy [137]. They showed that H2O2 treatment directly oxidized ATG3 (Cys264) and ATG7 (Cys572) instead of ATG4 to prevent LC3 lipidation. The discordance in these studies might be attributable to the difference of autophagy-inducing systems and ROS levels [85]. It was suggested that ATG3 and ATG7 might have higher redox sensitivity than ATG4. In detail, at low level of H2O2, ROS serve as signaling molecules to inhibit autophagy induction. When ROS reach higher levels, ATG4 oxidation becomes dominant, and promotes autophagy induction to prevent oxidative damage. However, this speculation needs further investigation.
Increasing evidence shows that the expression of ATG4 is aberrant in various types of tumors, suggesting it is a potential anticancer target. For example, exposure to cadmium (Cd) significantly increased ROS production, elevated ATG4 expression, activated autophagy and promoted cell growth, migration and invasion in human lung glandular cancer [138]. Another agonist of ATG4, flubendazole, has also been found to induce autophagic cell death and ROS production, leading to the inhibition of breast cancer cell growth [139]. Notably, a drug repurposing screening showed that tioconazole is an inhibitor of ATG4, which could stably occupy the active site of ATG4 in its open form to reduce the autophagic flux of cancer cells. Moreover, tioconazole suppressed tumor growth and sensitize tumor cells to starvation and chemotherapeutic drugs [140]. Similar findings were also observed in another ATG4 antagonist, the NSC185058, which negatively affected the development of osteosarcoma by inhibiting autophagy [141]. The above data indicate that both agonists and antagonists of ATG4 have tumor-therapeutic potential and once again demonstrate the dual role of autophagy. In the future drug discovery targeting ATG4, it may consider the type and stage of tumor and the specific role of ATG4. In conclusion, targeting ROS-dependent regulation of ATG4 for autophagy is a new approach for tumor treatment, and its specific molecular mechanism and targeting strategy need to be further investigated.

5.2. SQSTM1/p62

As mentioned above, ROS can increase the transcription of prototypic autophagy receptor SQSTM1/p62 and thus affect the autophagy process. Recently, it was found that two oxidation-sensitive cysteine residues in p62 could ungergo direct redox modification [142]. In response to the treatment of H2O2 or PR-619 (a redox cycler known to produce H2O2), the Cys105 and Cys113 were oxidized to promote the formation of p62 disulphide-linked conjugates (DLC), allowing p62-dependent aggresome formation. Furthermore, p62 oxidation and oligomerization was proved to promote autophagosome biogenesis and degradation of ubiquitylated autophagic cargoes, and activate pro-survival function of autophagy in stress conditions.
However, many issues regarding p62 oxidation and oligomerization remain to be resolved. For example, what is the potential molecular mechanism of DLC affecting the oligomerization of p62? In addition, redox sensitivity of p62 may occur in age-related pathology in humans, including aging, cancer and ischaemia/reperfusion injury. How the oxidation of p62 mediates autophagy and participates in disease processes still requires formal testing in vivo. Compared with p62/Keap1/Nrf2 pathway, whether p62 oxidation plays an antagonistic or synergistic role in cancer progression requires further investigation. Nevertheless, pro-survival autophagy mediated by p62 oxidation may also become a new anticancer target.

6. Cancer Therapy

In view of the contradictory roles of autophagy and ROS in cancer treatment, a series of clinical trials have been conducted. As shown in Figure 4, the first type is based on the observation that ROS induces protective autophagy leading to the drug resistance in tumor cells. The use of inhibitors of autophagy or antioxidants may enhance or restore the cytotoxicity effect of anticancer drugs [143]. To date, most pre-clinical studies and clinical trials support the use of the autophagy inhibitors chloroquine (CQ) or hydroxychloroquine (HCQ) in anticancer therapy, either as a single agent or in combination with other anticancer drugs [144]. One example is ciclopirox olamine (CPX), a potential anticancer agent, that has been demonstrated to induce cell protective autophagy through ROS-mediated JNK activation in human rhabdomyosarcoma (Rh30 and RD) cells. Chloroquine enhanced CPX-induced cell death, suggesting that the combination of autophagy inhibitors with CPX is a novel strategy for the treatment of rhabdomyosarcoma [145]. Similarly, antioxidants may be able to resverse tumor-drug resistance. For example, anticancer drug apogossypolone (ApoG2) could activate the ROS/JNK/ERK signaling pathway to induce protective autophagy in human hepatocellular carcinoma (HCC) cells, and the use of antioxidant (N-acetylcysteine, NAC) increased the sensitivity of HCC cells to ApoG2 [146]. Ginsenoside Rg3, the main active component of ginseng, has been reported to suppress proliferation and induce apoptosis of Lewis lung carcinoma (LLC) cells by reducing ROS levels [147]. When combining with cisplatin, Rg3 could prevent intracellular ROS accumulation induced by cisplatin, enhance the susceptibility of colorectal cancer cells to cisplatin [148]. Some other natural antioxidants such as resveratrol and carotenoid have also been reported to remove endogenously generated radicals and reduce the incidence of cancer [149,150,151,152]. However, in view of the dual roles of ROS in autophagy, the role of antioxidants also varies with genetic, epigenetic and microenvironmental variations [153]. There are some literatures reported that antioxidant supplementation during chemotherapy or radiotherapy reduced the survival time of patients [154]. One possible explanation is that the use of antioxidants weakens the cytotoxicity of antitumor drugs by inhibiting drug-induced ROS accumulation. Therefore, antioxidants as an anticancer strategy should be carefully considered before entering clinical use. In contrast, the second cancer therapy strategy is to exploit ROS and autophagy to achieve cytotoxicity. Ionizing radiation (IR) is one of the common means of cancer treatment, and it can exert cytotoxicity by producing ROS. Ionizing radiation has also been reported to induce autophagy in certain types of cancer cells, such as malignant glioma cells and pancreatic cancer cells [155,156]. In addition to ionizing radiation, some drugs were reported to stimulate ROS production to trigger autophagic cell death. 2-methoxyestradiol (2-ME), a natural metabolite of estradiol, has been identified as a promising anticancer agent [157]. Chen et al. found that 2-ME induced oxidative stress in the transformed cell line HEK293 and cancer cell lines U87 and HeLa, thereby increasing autophagy-induced cell death [158]. Similar data were obtained with bruceine D and resveratrol, both of which could induce apoptosis through ROS-triggered autophagy in lung cancer and colon cancer, respectively [159,160].
Determining the redox regulation of autophagy in tumor cells is an important and challenging endeavor. From the currently available reports, the cellular consequences of ROS-induced autophagy are cell type-specific and treatment-dependent. Therefore, researchers should implement precision or personalized medicine to provide tailored treatment for cancer patients. At present, several key issues need to be further solved, including finding simple and rapid approaches to quantify ROS and autophagy levels in vivo, exploring the exact mechanism of redox regulation of autophagy, and determining the most effective approaches to target ROS-mediated autophagy for cancer therapy [143,161]. Many known redox regulation mechanisms of autophagy still lack direct evidence in tumor cells, especially in tumor tissues. Only when the relationship between ROS, autophagy and cancer is fully understood can it be effectively exploited in pharmaceutical and medical research areas.

7. Conclusions and Perspectives

Both ROS and autophagy are thought to play double-edged roles in cancer. ROS act as both signaling and damaging molecules. Autophagy can rescue the cell from toxic stress, but it can cause autophagic cell death under certain conditions. Both ROS and autophagy are dysregulated in tumors, and it is also now widely accepted that ROS is involved in the regulation of autophagy, leading to tumor progression or tumor suppression. Here, we review the complex mechanism underlying redox regulation of autophagy in tumor cells and elucidates potential targets for the treatment of cancer. In conclusion, it is, therefore, now clear that future cancer treatment will move towards precision medicine with an extensive evaluation of the genetic or biochemical background of each patient and tumor category (tissue, stage, autophagy levels, ROS levels). Although many problems and challenges remain, new anticancer approaches targeting ROS-mediated autophagy will be continually developed to provide hope for cancer therapy.

Author Contributions

J.H., L.D. and K.W. contributed to the writing and editing process of the manuscript. J.H. and L.D. was involved in the creation of the figures. K.W. and L.L. came up with the original idea of the study, corrected and approved the final manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Chinese NSFC (81872277, 81821002, 82073081, 82002963, 82273122), Guangdong Basic and Applied Basic Research Foundation (2019B030302012), and 1·3·5 project of excellent development of discipline of West China Hospital of Sichuan University (ZYYC21001).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Dawane, J.S.; Pandit, V.A. Understanding Redox Homeostasis and Its Role in Cancer. J. Clin. Diagn. Res. 2012, 6, 1796. [Google Scholar] [CrossRef] [PubMed]
  2. Schieber, M.; Chandel, N.S. ROS Function in Redox Signaling and Oxidative Stress. Curr. Biol. 2014, 24, R453–R462. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Graves, D.B. The emerging role of reactive oxygen and nitrogen species in redox biology and some implications for plasma applications to medicine and biology. J. Phys. D Appl. Phys. 2012, 45, 263001. [Google Scholar] [CrossRef]
  4. Nimse, S.B.; Pal, D. Free radicals, natural antioxidants, and their reaction mechanisms. RSC Adv. 2015, 5, 27986. [Google Scholar] [CrossRef] [Green Version]
  5. Tan, S.; Sagara, Y.; Liu, Y.; Maher, P.; Schubert, D. The Regulation of Reactive Oxygen Species Production during Programmed Cell Death. J. Cell Biol. 1998, 141, 1423–1432. [Google Scholar] [CrossRef] [Green Version]
  6. Glick, D.; Barth, S.; MacLeod, K.F. Autophagy: Cellular and molecular mechanisms. J. Pathol. 2010, 221, 3–12. [Google Scholar] [CrossRef] [Green Version]
  7. Kroemer, G.; Mariño, G.; Levine, B. Autophagy and the Integrated Stress Response. Mol. Cell 2010, 40, 280–293. [Google Scholar] [CrossRef] [Green Version]
  8. Yun, C.W.; Lee, S.H. The Roles of Autophagy in Cancer. Int. J. Mol. Sci. 2018, 19, 3466. [Google Scholar] [CrossRef] [Green Version]
  9. Gao, M.; Hu, F.; Hu, M.; Hu, Y.; Shi, H.; Zhao, G.-J.; Jian, C.; Ji, Y.-X.; Zhang, X.-J.; She, Z.-G.; et al. Sophoricoside ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy. Biosci. Rep. 2020, 40. [Google Scholar] [CrossRef]
  10. Cheng, Y.; Ren, X.; Hait, W.N.; Yang, J.-M. Therapeutic Targeting of Autophagy in Disease: Biology and Pharmacology. Pharmacol. Rev. 2013, 65, 1162–1197. [Google Scholar] [CrossRef]
  11. Raza, M.H.; Siraj, S.; Arshad, A.; Waheed, U.; Aldakheel, F.; Alduraywish, S.; Arshad, M. ROS-modulated therapeutic approaches in cancer treatment. J. Cancer Res. Clin. Oncol. 2017, 143, 1789–1809. [Google Scholar] [CrossRef] [PubMed]
  12. Chio, I.I.C.; Tuveson, D.A. ROS in Cancer: The Burning Question. Trends Mol. Med. 2017, 23, 411–429. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Murphy, M.P. How mitochondria produce reactive oxygen species. Biochem. J. 2009, 417, 1–13. [Google Scholar] [CrossRef] [Green Version]
  14. Bedard, K.; Krause, K.-H. The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology. Physiol. Rev. 2007, 87, 245–313. [Google Scholar] [CrossRef] [PubMed]
  15. Lloyd, R.V.; Hanna, P.M.; Mason, R.P. The Origin of the Hydroxyl Radical Oxygen in the Fenton Reaction. Free. Radic. Biol. Med. 1997, 22, 885–888. [Google Scholar] [CrossRef] [PubMed]
  16. Brea, D.; Roquer, J.; Serena, J.; Segura, T.; Castillo, J. Oxidative stress markers are associated to vascular recurrence in non-cardioembolic stroke patients non-treated with statins. BMC Neurol. 2012, 12, 65. [Google Scholar] [CrossRef] [Green Version]
  17. Sarsour, E.H.; Kumar, M.G.; Chaudhuri, L.; Kalen, A.L.; Goswami, P.C. Redox Control of the Cell Cycle in Health and Disease. Antioxidants Redox Signal. 2009, 11, 2985–3011. [Google Scholar] [CrossRef]
  18. Blokhina, O.; Virolainen, E.; Fagerstedt, K.V. Antioxidants, Oxidative Damage and Oxygen Deprivation Stress: A Review. Ann. Bot. 2003, 91, 179–194. [Google Scholar] [CrossRef] [Green Version]
  19. Moloney, J.N.; Cotter, T.G. ROS signalling in the biology of cancer. Semin. Cell Dev. Biol. 2018, 80, 50–64. [Google Scholar] [CrossRef]
  20. Suzuki, H.; Sugiyama, Y. Excretion of GSSG and Glutathione Conjugates Mediated by MRP1 and CM0AT/MRP2. Semin. Liver Dis. 1998, 18, 359–376. [Google Scholar] [CrossRef]
  21. He, L.; He, T.; Farrar, S.; Ji, L.; Liu, T.; Ma, X. Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species. Cell. Physiol. Biochem. 2017, 44, 532–553. [Google Scholar] [CrossRef] [PubMed]
  22. Ehnert, S.; Fentz, A.-K.; Schreiner, A.; Birk, J.; Wilbrand, B.; Ziegler, P.; Reumann, M.K.; Wang, H.; Falldorf, K.; Nussler, A.K. Extremely low frequency pulsed electromagnetic fields cause antioxidative defense mechanisms in human osteoblasts via induction of •O2−and H2O2. Sci. Rep. 2017, 7, 14544. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Bacchetti, T.; Salvolini, E.; Pompei, V.; Campagna, R.; Molinelli, E.; Brisigotti, V.; Togni, L.; Lucarini, G.; Sartini, D.; Campanati, A.; et al. Paraoxonase-2: A potential biomarker for skin cancer aggressiveness. Eur. J. Clin. Investig. 2020, 51, e13452. [Google Scholar] [CrossRef] [PubMed]
  24. Sartini, D.; Campagna, R.; Lucarini, G.; Pompei, V.; Salvolini, E.; Mattioli-Belmonte, M.; Molinelli, E.; Brisigotti, V.; Campanati, A.; Bacchetti, T.; et al. Differential immunohistochemical expression of paraoxonase-2 in actinic keratosis and squamous cell carcinoma. Hum. Cell 2021, 34, 1929–1931. [Google Scholar] [CrossRef] [PubMed]
  25. Tseng, J.-H.; Chen, C.-Y.; Chen, P.-C.; Hsiao, S.-H.; Fan, C.-C.; Liang, Y.-C.; Chen, C.-P. Valproic acid inhibits glioblastoma multiforme cell growth via paraoxonase 2 expression. Oncotarget 2017, 8, 14666–14679. [Google Scholar] [CrossRef] [Green Version]
  26. Fumarola, S.; Cecati, M.; Sartini, D.; Ferretti, G.; Milanese, G.; Galosi, A.B.; Pozzi, V.; Campagna, R.; Morresi, C.; Emanuelli, M.; et al. Bladder Cancer Chemosensitivity Is Affected by Paraoxonase-2 Expression. Antioxidants 2020, 9, 175. [Google Scholar] [CrossRef] [Green Version]
  27. Campagna, R.; Bacchetti, T.; Salvolini, E.; Pozzi, V.; Molinelli, E.; Brisigotti, V.; Sartini, D.; Campanati, A.; Ferretti, G.; Offidani, A.; et al. Paraoxonase-2 Silencing Enhances Sensitivity of A375 Melanoma Cells to Treatment with Cisplatin. Antioxidants 2020, 9, 1238. [Google Scholar] [CrossRef]
  28. Bacchetti, T.; Campagna, R.; Sartini, D.; Cecati, M.; Morresi, C.; Bellachioma, L.; Martinelli, E.; Rocchetti, G.; Lucini, L.; Ferretti, G.; et al. C. spinosa L. subsp. rupestris Phytochemical Profile and Effect on Oxidative Stress in Normal and Cancer Cells. Molecules 2022, 27, 6488. [Google Scholar] [CrossRef]
  29. Wang, K.; Jiang, J.; Lei, Y.; Zhou, S.; Wei, Y.; Huang, C. Targeting Metabolic–Redox Circuits for Cancer Therapy. Trends Biochem. Sci. 2019, 44, 401–414. [Google Scholar] [CrossRef]
  30. Tossetta, G.; Marzioni, D. Natural and synthetic compounds in Ovarian Cancer: A focus on NRF2/KEAP1 pathway. Pharmacol. Res. 2022, 183, 106365. [Google Scholar] [CrossRef]
  31. Peus, D.; Vasa, R.A.; Beyerle, A.; Meves, A.; Krautmacher, C.; Pittelkow, M.R. UVB Activates ERK1/2 and p38 Signaling Pathways via Reactive Oxygen Species in Cultured Keratinocytes. J. Investig. Dermatol. 1999, 112, 751–756. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Ma, Z.; Liu, X.; Zhang, Q.; Yu, Z.; Gao, D. Carvedilol suppresses malignant proliferation of mammary epithelial cells through inhibition of the ROS-mediated PI3K/AKT signaling pathway. Oncol. Rep. 2018, 41, 811–818. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Liou, G.-Y.; Döppler, H.; DelGiorno, K.E.; Zhang, L.; Leitges, M.; Crawford, H.C.; Murphy, M.P.; Storz, P. Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions. Cell Rep. 2016, 14, 2325–2336. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Méplan, C.; Richard, M.-J.; Hainaut, P. Redox signalling and transition metals in the control of the p53 pathway. Biochem. Pharmacol. 1999, 59, 25–33. [Google Scholar] [CrossRef] [PubMed]
  35. Fourquet, S.; Guerois, R.; Biard, D.; Toledano, M.B. Activation of NRF2 by Nitrosative Agents and H2O2 Involves KEAP1 Disulfide Formation. J. Biol. Chem. 2010, 285, 8463–8471. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Weinberg, F.; Ramnath, N.; Nagrath, D. Reactive Oxygen Species in the Tumor Microenvironment: An Overview. Cancers 2019, 11, 1191. [Google Scholar] [CrossRef] [Green Version]
  37. Yodkeeree, S.; Sung, B.; Limtrakul, P.; Aggarwal, B.B. Zerumbone Enhances TRAIL-Induced Apoptosis through the Induction of Death Receptors in Human Colon Cancer Cells: Evidence for an Essential Role of Reactive Oxygen Species. Cancer Res. 2009, 69, 6581–6589. [Google Scholar] [CrossRef] [Green Version]
  38. Wong, Y.T.; Ruan, R.; Tay, F.E.H. Relationship between levels of oxidative DNA damage, lipid peroxidation and mitochondrial membrane potential in young and old F344 rats. Free. Radic. Res. 2006, 40, 393–402. [Google Scholar] [CrossRef]
  39. Porporato, P.E.; Payen, V.L.; Pérez-Escuredo, J.; De Saedeleer, C.J.; Danhier, P.; Copetti, T.; Dhup, S.; Tardy, M.; Vazeille, T.; Bouzin, C.; et al. A Mitochondrial Switch Promotes Tumor Metastasis. Cell Rep. 2014, 8, 754–766. [Google Scholar] [CrossRef] [Green Version]
  40. Piskounova, E.; Agathocleous, M.; Murphy, M.M.; Hu, Z.; Huddlestun, S.E.; Zhao, Z.; Leitch, A.M.; Johnson, T.M.; DeBerardinis, R.J.; Morrison, S.J. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 2015, 527, 186–191. [Google Scholar] [CrossRef]
  41. Zhao, Y.G.; Chen, Y.; Miao, G.; Zhao, H.; Qu, W.; Li, D.; Wang, Z.; Liu, N.; Li, L.; Chen, S.; et al. The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates SERCA Activity to Control ER-Isolation Membrane Contacts for Autophagosome Formation. Mol. Cell 2017, 67, 974–989.e6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Dikic, I.; Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 2018, 19, 349–364. [Google Scholar] [CrossRef] [PubMed]
  43. Jung, C.H.; Jun, C.B.; Ro, S.-H.; Kim, Y.-M.; Otto, N.M.; Cao, J.; Kundu, M.; Kim, D.-H. ULK-Atg13-FIP200 Complexes Mediate mTOR Signaling to the Autophagy Machinery. Mol. Biol. Cell 2009, 20, 1992–2003. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Hurley, J.H.; Young, L.N. Mechanisms of Autophagy Initiation. Annu. Rev. Biochem. 2017, 86, 225–244. [Google Scholar] [CrossRef]
  45. Cao, W.; Li, J.; Yang, K.; Cao, D. An overview of autophagy: Mechanism, regulation and research progress. Bull. Cancer 2021, 108, 304–322. [Google Scholar] [CrossRef] [PubMed]
  46. Nakamura, S.; Yoshimori, T. Autophagy and Longevity. Mol. Cells 2018, 41, 65–72. [Google Scholar] [CrossRef] [PubMed]
  47. Tanida, I.; Ueno, T.; Kominami, E. LC3 and Autophagy. Methods Mol. Biol. 2008, 445, 77–88. [Google Scholar]
  48. Navarro-Yepes, J.; Burns, M.; Anandhan, A.; Khalimonchuk, O.; del Razo, L.M.; Quintanilla-Vega, B.; Pappa, A.; Panayiotidis, M.I.; Franco, R. Oxidative Stress, Redox Signaling, and Autophagy: Cell Death Versus Survival. Antioxidants Redox Signal. 2014, 21, 66–85. [Google Scholar] [CrossRef] [Green Version]
  49. Dooley, H.C.; Razi, M.; Polson, H.E.; Girardin, S.E.; Wilson, M.I.; Tooze, S.A. WIPI2 Links LC3 Conjugation with PI3P, Autophagosome Formation, and Pathogen Clearance by Recruiting Atg12–5-16L1. Mol. Cell 2014, 55, 238–252. [Google Scholar] [CrossRef] [Green Version]
  50. Nieto-Torres, J.L.; Leidal, A.M.; Debnath, J.; Hansen, M. Beyond Autophagy: The Expanding Roles of ATG8 Proteins. Trends Biochem. Sci. 2021, 46, 673–686. [Google Scholar] [CrossRef]
  51. Zhao, Y.G.; Codogno, P.; Zhang, H. Machinery, regulation and pathophysiological implications of autophagosome maturation. Nat. Rev. Mol. Cell Biol. 2021, 22, 733–750. [Google Scholar] [CrossRef] [PubMed]
  52. Itakura, E.; Kishi-Itakura, C.; Mizushima, N. The Hairpin-type Tail-Anchored SNARE Syntaxin 17 Targets to Autophagosomes for Fusion with Endosomes/Lysosomes. Cell 2012, 151, 1256–1269. [Google Scholar] [CrossRef] [Green Version]
  53. Zhou, C.; Wu, Z.; Du, W.; Que, H.; Wang, Y.; Ouyang, Q.; Jian, F.; Yuan, W.; Zhao, Y.; Tian, R.; et al. Recycling of autophagosomal components from autolysosomes by the recycler complex. Nature 2022, 24, 497–512. [Google Scholar] [CrossRef] [PubMed]
  54. Liang, X.H.; Jackson, S.; Seaman, M.; Brown, K.; Kempkes, B.; Hibshoosh, H.; Levine, B. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999, 402, 672–676. [Google Scholar] [CrossRef]
  55. Maiuri, M.C.; Le Toumelin, G.; Criollo, A.; Rain, J.-C.; Gautier, F.; Juin, P.; Tasdemir, E.; Pierron, G.; Troulinaki, K.; Tavernarakis, N.; et al. Functional and physical interaction between Bcl-XL and a BH3-like domain in Beclin-1. EMBO J. 2007, 26, 2527–2539. [Google Scholar] [CrossRef]
  56. Lefranc, F.; Facchini, V.; Kiss, R. Proautophagic Drugs: A Novel Means to Combat Apoptosis-Resistant Cancers, with a Special Emphasis on Glioblastomas. Oncologist 2007, 12, 1395–1403. [Google Scholar] [CrossRef]
  57. Degenhardt, K.; Mathew, R.; Beaudoin, B.; Bray, K.; Anderson, D.; Chen, G.; Mukherjee, C.; Shi, Y.; Gélinas, C.; Fan, Y.; et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006, 10, 51–64. [Google Scholar] [CrossRef] [Green Version]
  58. Kimmelman, A.C.; White, E. Autophagy and Tumor Metabolism. Cell Metab. 2017, 25, 1037–1043. [Google Scholar] [CrossRef]
  59. Chen, S.; Rehman, S.K.; Zhang, W.; Wen, A.; Yao, L.; Zhang, J. Autophagy is a therapeutic target in anticancer drug resistance. Biochim. Biophys. Acta (BBA) Bioenerg. 2010, 1806, 220–229. [Google Scholar] [CrossRef] [PubMed]
  60. Vazquez-Martin, A.; Oliveras-Ferraros, C.; Menendez, J.A. Autophagy Facilitates the Development of Breast Cancer Resistance to the Anti-HER2 Monoclonal Antibody Trastuzumab. PLoS ONE 2009, 4, e6251. [Google Scholar] [CrossRef] [Green Version]
  61. Holmström, K.M.; Finkel, T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat. Rev. Mol. Cell Biol. 2014, 15, 411–421. [Google Scholar] [CrossRef]
  62. Ren, F.; Wang, K.; Zhang, T.; Jiang, J.; Nice, E.C.; Huang, C. New insights into redox regulation of stem cell self-renewal and differentiation. Biochim. Biophys. 2015, 1850, 1518–1526. [Google Scholar] [CrossRef]
  63. Filomeni, G.; De Zio, D.; Cecconi, F. Oxidative stress and autophagy: The clash between damage and metabolic needs. Cell Death Differ. 2015, 22, 377–388. [Google Scholar] [CrossRef] [Green Version]
  64. Simon, H.-U.; Friis, R.; Tait, S.W.G.; Ryan, K.M. Retrograde signaling from autophagy modulates stress responses. Sci. Signal. 2017, 10, eaag2791. [Google Scholar] [CrossRef] [Green Version]
  65. Kim, Y.C.; Guan, K.-L. mTOR: A pharmacologic target for autophagy regulation. J. Clin. Investig. 2015, 125, 25–32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Kim, J.; Kundu, M.; Viollet, B.; Guan, K.-L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 2011, 13, 132–141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Xu, Z.; Han, X.; Ou, D.; Liu, T.; Li, Z.; Jiang, G.; Liu, J.; Zhang, J. Targeting PI3K/AKT/mTOR-mediated autophagy for tumor therapy. Appl. Microbiol. Biotechnol. 2019, 104, 575–587. [Google Scholar] [CrossRef] [PubMed]
  68. Heras-Sandoval, D.; Pérez-Rojas, J.M.; Hernández-Damián, J.; Pedraza-Chaverri, J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell. Signal. 2014, 26, 2694–2701. [Google Scholar] [CrossRef] [PubMed]
  69. Carnero, A.; Blanco-Aparicio, C.; Renner, O.; Link, W.; Leal, J.F. The PTEN/PI3K/AKT Signalling Pathway in Cancer, Therapeutic Implications. Curr. Cancer Drug Targets 2008, 8, 187–198. [Google Scholar] [CrossRef]
  70. Pópulo, H.; Lopes, J.M.; Soares, P. The mTOR Signalling Pathway in Human Cancer. Int. J. Mol. Sci. 2012, 13, 1886–1918. [Google Scholar] [CrossRef] [Green Version]
  71. Lin, S.-C.; Hardie, D.G. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metab. 2017, 27, 299–313. [Google Scholar] [CrossRef] [PubMed]
  72. Zmijewski, J.W.; Banerjee, S.; Bae, H.; Friggeri, A.; Lazarowski, E.R.; Abraham, E. Exposure to Hydrogen Peroxide Induces Oxidation and Activation of AMP-activated Protein Kinase*. J. Biol. Chem. 2010, 285, 33154–33164. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Wu, X.; Luo, P.; Rao, W.; Dai, S.; Zhang, L.; Ma, W.; Pu, J.; Yu, Y.; Wang, J.; Fei, Z. Homer1a Attenuates Hydrogen Peroxide-Induced Oxidative Damage in HT-22 Cells through AMPK-Dependent Autophagy. Front. Neurosci. 2018, 12, 51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Cardaci, S.; Filomeni, G.; Ciriolo, M.R. Redox implications of AMPK-mediated signal transduction beyond energetic clues. J. Cell Sci. 2012, 125, 2115–2125. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Zhao, Y.; Hu, X.; Liu, Y.; Dong, S.; Wen, Z.; He, W.; Zhang, S.; Huang, Q.; Shi, M. ROS signaling under metabolic stress: Cross-talk between AMPK and AKT pathway. Mol. Cancer 2017, 16, 79. [Google Scholar] [CrossRef] [Green Version]
  76. Staal, S.P. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: Amplification of AKT1 in a primary human gastric adenocarcinoma. Proc. Natl. Acad. Sci. USA 1987, 84, 5034–5037. [Google Scholar] [CrossRef] [Green Version]
  77. Ueno, T.; Sato, W.; Horie, Y.; Komatsu, M.; Tanida, I.; Yoshida, M.; Ohshima, S.; Mak, T.W.; Watanabe, S.; Kominami, E. Loss of Pten, a tumor suppressor, causes the strong inhibition of autophagy without affecting LC3 lipidation. Autophagy 2008, 4, 692–700. [Google Scholar] [CrossRef] [Green Version]
  78. Leslie, N.R.; Bennett, D.; Lindsay, Y.E.; Stewart, H.; Gray, A.; Downes, C. Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J. 2003, 22, 5501–5510. [Google Scholar] [CrossRef]
  79. Lee, S.-R.; Yang, K.-S.; Kwon, J.; Lee, C.; Jeong, W.; Rhee, S.G. Reversible Inactivation of the Tumor Suppressor PTEN by H2O2. J. Biol. Chem. 2002, 277, 20336–20342. [Google Scholar] [CrossRef] [Green Version]
  80. Murata, H.; Ihara, Y.; Nakamura, H.; Yodoi, J.; Sumikawa, K.; Kondo, T. Glutaredoxin Exerts an Antiapoptotic Effect by Regulating the Redox State of Akt. J. Biol. Chem. 2003, 278, 50226–50233. [Google Scholar] [CrossRef] [Green Version]
  81. Alexander, A.; Cai, S.-L.; Kim, J.; Nanez, A.; Sahin, M.; MacLean, K.H.; Inoki, K.; Guan, K.-L.; Shen, J.; Person, M.D.; et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc. Natl. Acad. Sci. USA 2010, 107, 4153–4158. [Google Scholar] [CrossRef]
  82. Guo, Z.; Kozlov, S.; Lavin, M.F.; Person, M.D.; Paull, T.T. ATM Activation by Oxidative Stress. Science 2010, 330, 517–521. [Google Scholar] [CrossRef] [Green Version]
  83. Moriwaki, T.; Yamasaki, A.; Zhang-Akiyama, Q.-M. ATM Induces Cell Death with Autophagy in Response to H2O2 Specifically in Caenorhabditis elegans Nondividing Cells. Oxidative Med. Cell. Longev. 2018, 2018, 3862070. [Google Scholar] [CrossRef] [PubMed]
  84. Zhang, J.; Tripathi, D.; Jing, J.; Alexander, A.; Kim, J.; Powell, R.T.; Dere, R.; Tait-Mulder, J.; Lee, J.-H.; Paull, T.T.; et al. ATM functions at the peroxisome to induce pexophagy in response to ROS. Nature 2015, 17, 1259–1269. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Zhou, J.; Li, X.-Y.; Liu, Y.-J.; Feng, J.; Wu, Y.; Shen, H.-M.; Lu, G.-D. Full-coverage regulations of autophagy by ROS: From induction to maturation. Autophagy 2021, 18, 1240–1255. [Google Scholar] [CrossRef] [PubMed]
  86. Sarkar, S.; Korolchuk, V.I.; Renna, M.; Imarisio, S.; Fleming, A.; Williams, A.; Garcia-Arencibia, M.; Rose, C.; Luo, S.; Underwood, B.R.; et al. Complex Inhibitory Effects of Nitric Oxide on Autophagy. Mol. Cell 2011, 43, 19–32. [Google Scholar] [CrossRef] [Green Version]
  87. Tripathi, D.N.; Chowdhury, R.; Trudel, L.J.; Tee, A.R.; Slack, R.S.; Walker, C.L.; Wogan, G.N. Reactive nitrogen species regulate autophagy through ATM-AMPK-TSC2–mediated suppression of mTORC1. Proc. Natl. Acad. Sci. USA 2013, 110, E2950–E2957. [Google Scholar] [CrossRef] [Green Version]
  88. Oka, S.-I.; Chin, A.; Park, J.Y.; Ikeda, S.; Mizushima, W.; Ralda, G.; Zhai, P.; Tong, M.; Byun, J.; Tang, F.; et al. Thioredoxin-1 maintains mitochondrial function via mechanistic target of rapamycin signalling in the heart. Cardiovasc. Res. 2019, 116, 1742–1755. [Google Scholar] [CrossRef]
  89. Xu, H.-D.; Qin, Z.-H. Beclin 1, Bcl-2 and Autophagy. Adv. Exp. Med. Biol. 2019, 1206, 109–126. [Google Scholar] [CrossRef]
  90. Adams, J.M.; Cory, S. Bcl-2-regulated apoptosis: Mechanism and therapeutic potential. Curr. Opin. Immunol. 2007, 19, 488–496. [Google Scholar] [CrossRef] [Green Version]
  91. Huang, J.-J.; Li, H.-R.; Huang, Y.; Jiang, W.-Q.; Xu, R.-H.; Huang, H.-Q.; Lv, Y.; Xia, Z.-J.; Zhu, X.-F.; Lin, T.-Y.; et al. Beclin 1 expression: A predictor of prognosis in patients with extranodal natural killer T-cell lymphoma, nasal type. Autophagy 2010, 6, 777–783. [Google Scholar] [CrossRef] [PubMed]
  92. Ehsan, N.A.; Mosbeh, A.M.; Elkhadry, S.W.; Gomaa, A.I.; Elsabaawy, M.M.; Elazab, D.S. Altered Protein and Gene Expression of Beclin-1 Correlates with Poor Prognosis of Hcv-Associated Hepatocellular Carcinoma in Egyptian Patients. Asian Pac. J. Cancer Prev. 2021, 22, 1115–1122. [Google Scholar] [CrossRef] [PubMed]
  93. Oh, S.; Ni, D.; Pirooz, S.D.; Lee, J.-Y.; Lee, D.; Zhao, Z.; Lee, S.; Lee, H.; Ku, B.; Kowalik, T.; et al. Downregulation of autophagy by Bcl-2 promotes MCF7 breast cancer cell growth independent of its inhibition of apoptosis. Cell Death Differ. 2010, 18, 452–464. [Google Scholar] [CrossRef] [PubMed]
  94. Wei, Y.; Pattingre, S.; Sinha, S.; Bassik, M.; Levine, B. JNK1-Mediated Phosphorylation of Bcl-2 Regulates Starvation-Induced Autophagy. Mol. Cell 2008, 30, 678–688. [Google Scholar] [CrossRef] [Green Version]
  95. Bandyopadhyay, S.; Chiang, C.-Y.; Srivastava, J.; Gersten, M.; White, S.; Bell, R.; Kurschner, C.; Martin, C.H.; Smoot, M.; Sahasrabudhe, S.; et al. A human MAP kinase interactome. Nat. Methods 2010, 7, 801–805. [Google Scholar] [CrossRef] [Green Version]
  96. Kamata, H.; Honda, S.-I.; Maeda, S.; Chang, L.; Hirata, H.; Karin, M. Reactive Oxygen Species Promote TNFα-Induced Death and Sustained JNK Activation by Inhibiting MAP Kinase Phosphatases. Cell 2005, 120, 649–661. [Google Scholar] [CrossRef] [Green Version]
  97. Wong, C.H.; Iskandar, K.B.; Yadav, S.K.; Hirpara, J.L.; Loh, T.; Pervaiz, S. Simultaneous Induction of Non-Canonical Autophagy and Apoptosis in Cancer Cells by ROS-Dependent ERK and JNK Activation. PLoS ONE 2010, 5, e9996. [Google Scholar] [CrossRef] [Green Version]
  98. Kim, M.-J.; Woo, S.-J.; Yoon, C.-H.; Lee, J.-S.; An, S.; Choi, Y.-H.; Hwang, S.-G.; Yoon, G.; Lee, S.-J. Involvement of Autophagy in Oncogenic K-Ras-induced Malignant Cell Transformation. J. Biol. Chem. 2011, 286, 12924–12932. [Google Scholar] [CrossRef] [Green Version]
  99. Liu, Y.; Min, W. Thioredoxin Promotes ASK1 Ubiquitination and Degradation to Inhibit ASK1-Mediated Apoptosis in a Redox Activity-Independent Manner. Circ. Res. 2002, 90, 1259–1266. [Google Scholar] [CrossRef] [Green Version]
  100. Shen, H.-M.; Liu, Z.-G. JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species. Free. Radic. Biol. Med. 2006, 40, 928–939. [Google Scholar] [CrossRef]
  101. Song, J.; Lee, Y.J. Differential role of glutaredoxin and thioredoxin in metabolic oxidative stress-induced activation of apoptosis signal-regulating kinase 1. Biochem. J. 2003, 373, 845–853. [Google Scholar] [CrossRef]
  102. Park, H.-S.; Huh, S.-H.; Kim, M.-S.; Lee, S.H.; Choi, E.-J. Nitric oxide negatively regulates c-Jun N-terminal kinase/stress-activated protein kinase by means of S-nitrosylation. Proc. Natl. Acad. Sci. USA 2000, 97, 14382–14387. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Nah, J.; Yoo, S.-M.; Jung, S.; Jeong, E.I.; Park, M.; Kaang, B.-K.; Jung, Y.-K. Phosphorylated CAV1 activates autophagy through an interaction with BECN1 under oxidative stress. Cell Death Dis. 2017, 8, e2822. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Wang, Q.; Guo, W.; Hao, B.; Shi, X.; Lu, Y.; Wong, C.W.; Ma, V.W.; Yip, T.T.; Au, J.S.; Hao, Q.; et al. Mechanistic study of TRPM2-Ca2+-CAMK2-BECN1 signaling in oxidative stress-induced autophagy inhibition. Autophagy 2016, 12, 1340–1354. [Google Scholar] [CrossRef] [Green Version]
  105. Eisenberg-Lerner, A.; Kimchi, A. PKD is a kinase of Vps34 that mediates ROS-induced autophagy downstream of DAPk. Cell Death Differ. 2011, 19, 788–797. [Google Scholar] [CrossRef]
  106. Shrivastava, A.; Kuzontkoski, P.M.; Groopman, J.E.; Prasad, A. Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-talk between Apoptosis and Autophagy. Mol. Cancer Ther. 2011, 10, 1161–1172. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Sajadimajd, S.; Khazaei, M. Oxidative Stress and Cancer: The Role of Nrf2. Curr. Cancer Drug Targets 2018, 18, 538–557. [Google Scholar] [CrossRef] [PubMed]
  108. Jaramillo, M.C.; Zhang, D.D. The emerging role of the Nrf2–Keap1 signaling pathway in cancer. Genes Dev. 2013, 27, 2179–2191. [Google Scholar] [CrossRef] [Green Version]
  109. Li, L.; Tan, J.; Miao, Y.; Lei, P.; Zhang, Q. ROS and Autophagy: Interactions and Molecular Regulatory Mechanisms. Cell. Mol. Neurobiol. 2015, 35, 615–621. [Google Scholar] [CrossRef]
  110. Ichimura, Y.; Waguri, S.; Sou, Y.-S.; Kageyama, S.; Hasegawa, J.; Ishimura, R.; Saito, T.; Yang, Y.; Kouno, T.; Fukutomi, T.; et al. Phosphorylation of p62 Activates the Keap1-Nrf2 Pathway during Selective Autophagy. Mol. Cell 2013, 51, 618–631. [Google Scholar] [CrossRef] [Green Version]
  111. Jiang, T.; Harder, B.; Rojo de la Vega, M.; Wong, P.K.; Chapman, E.; Zhang, D.D. p62 links autophagy and Nrf2 signaling. Free Radic. Biol. Med. 2015, 88 Pt B, 199–204. [Google Scholar] [CrossRef]
  112. Mathew, R.; Karp, C.M.; Beaudoin, B.; Vuong, N.; Chen, G.; Chen, H.-Y.; Bray, K.; Reddy, A.; Bhanot, G.; Gelinas, C.; et al. Autophagy Suppresses Tumorigenesis through Elimination of p62. Cell 2009, 137, 1062–1075. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Inami, Y.; Waguri, S.; Sakamoto, A.; Kouno, T.; Nakada, K.; Hino, O.; Watanabe, S.; Ando, J.; Iwadate, M.; Yamamoto, M.; et al. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J. Cell Biol. 2011, 193, 275–284. [Google Scholar] [CrossRef] [Green Version]
  114. Islam, M.A.; Sooro, M.A.; Zhang, P. Autophagic Regulation of p62 is Critical for Cancer Therapy. Int. J. Mol. Sci. 2018, 19, 1405. [Google Scholar] [CrossRef] [Green Version]
  115. Marzioni, D.; Mazzucchelli, R.; Fantone, S.; Tossetta, G. NRF2 modulation in TRAMP mice: An in vivo model of prostate cancer. Mol. Biol. Rep. 2022, 1–9. [Google Scholar] [CrossRef] [PubMed]
  116. Zhitomirsky, B.; Yunaev, A.; Kreiserman, R.; Kaplan, A.; Stark, M.; Assaraf, Y.G. Lysosomotropic drugs activate TFEB via lysosomal membrane fluidization and consequent inhibition of mTORC1 activity. Cell Death Dis. 2018, 9, 1–15. [Google Scholar] [CrossRef] [Green Version]
  117. Martina, J.A.; Puertollano, R. Rag GTPases mediate amino acid–dependent recruitment of TFEB and MITF to lysosomes. J. Cell Biol. 2013, 200, 475–491. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Roczniak-Ferguson, A.; Petit, C.S.; Froehlich, F.; Qian, S.; Ky, J.; Angarola, B.; Walther, T.C.; Ferguson, S.M. The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis. Sci. Signal. 2012, 5, ra42. [Google Scholar] [CrossRef] [Green Version]
  119. Wang, H.; Wang, N.; Xu, D.; Ma, Q.; Chen, Y.; Xu, S.; Xia, Q.; Zhang, Y.; Prehn, J.H.M.; Wang, G.; et al. Oxidation of multiple MiT/TFE transcription factors links oxidative stress to transcriptional control of autophagy and lysosome biogenesis. Autophagy 2019, 16, 1683–1696. [Google Scholar] [CrossRef]
  120. Zeng, W.; Xiao, T.; Cai, A.; Cai, W.; Liu, H.; Liu, J.; Li, J.; Tan, M.; Xie, L.; Liu, Y.; et al. Inhibiting ROS-TFEB-Dependent Autophagy Enhances Salidroside-Induced Apoptosis in Human Chondrosarcoma Cells. Cell. Physiol. Biochem. 2017, 43, 1487–1502. [Google Scholar] [CrossRef] [Green Version]
  121. Jiang, X.; Wang, J.; Deng, X.; Xiong, F.; Zhang, S.; Gong, Z.; Li, X.; Cao, K.; Deng, H.; He, Y.; et al. The role of microenvironment in tumor angiogenesis. J. Exp. Clin. Cancer Res. 2020, 39, 204. [Google Scholar] [CrossRef] [PubMed]
  122. Masoud, G.N.; Li, W. HIF-1α pathway: Role, regulation and intervention for cancer therapy. Acta Pharm. Sin. B 2015, 5, 378–389. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Scherz-Shouval, R.; Elazar, Z. Regulation of autophagy by ROS: Physiology and pathology. Trends Biochem. Sci. 2011, 36, 30–38. [Google Scholar] [CrossRef]
  124. Mazure, N.M.; Pouysségur, J. Hypoxia-induced autophagy: Cell death or cell survival? Curr. Opin. Cell Biol. 2010, 22, 177–180. [Google Scholar] [CrossRef]
  125. Kobayashi, Y.; Oguro, A.; Imaoka, S. Feedback of hypoxia-inducible factor-1alpha (HIF-1alpha) transcriptional activity via redox factor-1 (Ref-1) induction by reactive oxygen species (ROS). Free Radic. Res. 2021, 55, 154–164. [Google Scholar] [CrossRef]
  126. Yang, R.; Dunn, J.F. Multiple sclerosis disease progression: Contributions from a hypoxia–inflammation cycle. Mult. Scler. J. 2018, 25, 1715–1718. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Zhang, Y.; Liu, D.; Hu, H.; Zhang, P.; Xie, R.; Cui, W. HIF-1α/BNIP3 signaling pathway-induced-autophagy plays protective role during myocardial ischemia-reperfusion injury. Biomed. Pharmacother. 2019, 120, 109464. [Google Scholar] [CrossRef]
  128. Yasinska, I.M.; Sumbayev, V.V. S-nitrosation of Cys-800 of HIF-1α protein activates its interaction with p300 and stimulates its transcriptional activity. FEBS Lett. 2003, 549, 105–109. [Google Scholar] [CrossRef] [Green Version]
  129. Fu, Y.; Huang, Z.; Hong, L.; Lu, J.-H.; Feng, D.; Yin, X.-M.; Li, M. Targeting ATG4 in Cancer Therapy. Cancers 2019, 11, 649. [Google Scholar] [CrossRef] [Green Version]
  130. Satoo, K.; Noda, N.N.; Kumeta, H.; Fujioka, Y.; Mizushima, N.; Ohsumi, Y.; Inagaki, F. The structure of Atg4B–LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy. EMBO J. 2009, 28, 1341–1350. [Google Scholar] [CrossRef]
  131. Yu, Z.-Q.; Ni, T.; Hong, B.; Wang, H.-Y.; Jiang, F.-J.; Zou, S.; Chen, Y.; Zheng, X.-L.; Klionsky, D.J.; Liang, Y.; et al. Dual roles of Atg8−PE deconjugation by Atg4 in autophagy. Autophagy 2012, 8, 883–892. [Google Scholar] [CrossRef] [PubMed]
  132. Scherz-Shouval, R.; Sagiv, Y.; Shorer, H.; Elazar, Z. The COOH Terminus of GATE-16, an Intra-Golgi Transport Modulator, Is Cleaved by the Human Cysteine Protease HsApg4A. J. Biol. Chem. 2003, 278, 14053–14058. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Scherz-Shouval, R.; Shvets, E.; Fass, E.; Shorer, H.; Gil, L.; Elazar, Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 2007, 26, 1749–1760. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Pérez-Pérez, M.E.; Zaffagnini, M.; Marchand, C.H.; Crespo, J.L.; Lemaire, S.D. The yeast autophagy protease Atg4 is regulated by thioredoxin. Autophagy 2014, 10, 1953–1964. [Google Scholar] [CrossRef] [Green Version]
  135. Zheng, X.; Yang, Z.; Gu, Q.; Xia, F.; Fu, Y.; Liu, P.; Yin, X.-M.; Li, M. The protease activity of human ATG4B is regulated by reversible oxidative modification. Autophagy 2020, 16, 1838–1850. [Google Scholar] [CrossRef] [PubMed]
  136. Li, Y.; Zhang, Y.; Wang, L.; Wang, P.; Xue, Y.; Li, X.; Qiao, X.; Zhang, X.; Xu, T.; Liu, G.-H.; et al. Autophagy impairment mediated by S-nitrosation of ATG4B leads to neurotoxicity in response to hyperglycemia. Autophagy 2017, 13, 1145–1160. [Google Scholar] [CrossRef] [Green Version]
  137. Frudd, K.; Burgoyne, T.; Burgoyne, J.R. Oxidation of Atg3 and Atg7 mediates inhibition of autophagy. Nat. Commun. 2018, 9, 95. [Google Scholar] [CrossRef] [Green Version]
  138. Lv, W.; Sui, L.; Yan, X.; Xie, H.; Jiang, L.; Geng, C.; Li, Q.; Yao, X.; Kong, Y.; Cao, J. ROS-dependent Atg4 upregulation mediated autophagy plays an important role in Cd-induced proliferation and invasion in A549 cells. Chem. Interact. 2018, 279, 136–144. [Google Scholar] [CrossRef]
  139. Zhang, L.; Guo, M.; Li, J.; Zheng, Y.; Zhang, S.; Xie, T.; Liu, B. Systems biology-based discovery of a potential Atg4B agonist (Flubendazole) that induces autophagy in breast cancer. Mol. Biosyst. 2015, 11, 2860–2866. [Google Scholar] [CrossRef]
  140. Liu, P.-F.; Tsai, K.-L.; Hsu, C.-J.; Tsai, W.-L.; Cheng, J.-S.; Chang, H.-W.; Shiau, C.-W.; Goan, Y.-G.; Tseng, H.-H.; Wu, C.-H.; et al. Drug Repurposing Screening Identifies Tioconazole as an ATG4 Inhibitor that Suppresses Autophagy and Sensitizes Cancer Cells to Chemotherapy. Theranostics 2018, 8, 830–845. [Google Scholar] [CrossRef]
  141. Akin, D.; Wang, S.K.; Habibzadegah-Tari, P.; Law, B.; Ostrov, D.; Li, M.; Yin, X.-M.; Kim, J.-S.; Horenstein, N.; Dunn, W.A.D., Jr. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy 2014, 10, 2021–2035. [Google Scholar] [CrossRef] [PubMed]
  142. Carroll, B.; Otten, E.G.; Manni, D.; Stefanatos, R.; Menzies, F.M.; Smith, G.R.; Jurk, D.; Kenneth, N.; Wilkinson, S.; Passos, J.F.; et al. Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis. Nat. Commun. 2018, 9, 256. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Poillet-Perez, L.; Despouy, G.; Delage-Mourroux, R.; Boyer-Guittaut, M. Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy. Redox Biol. 2015, 4, 184–192. [Google Scholar] [CrossRef] [Green Version]
  144. De Sanctis, J.B.; Charris, J.; Blanco, Z.; Ramírez, H.; Martínez, G.P.; Mijares, M.R. Molecular Mechanisms of Chloroquine and Hydroxychloroquine use in Cancer Therapy. Anti-Cancer Agents Med. Chem. 2022. [Google Scholar] [CrossRef] [PubMed]
  145. Zhou, H.; Shen, T.; Shang, C.; Luo, Y.; Liu, L.; Yan, J.; Li, Y.; Huang, S. Ciclopirox induces autophagy through reactive oxygen species-mediated activation of JNK signaling pathway. Oncotarget 2014, 5, 10140–10150. [Google Scholar] [CrossRef] [Green Version]
  146. Cheng, P.; Ni, Z.; Dai, X.; Wang, B.; Ding, W.; Smith, A.R.; Xu, L.; Wu, D.; He, F.; Lian, J. The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular carcinoma cells. Cell Death Dis. 2013, 4, e489. [Google Scholar] [CrossRef] [Green Version]
  147. Sun, H.Y.; Lee, J.H.; Han, Y.-S.; Yoon, Y.M.; Yun, C.W.; Kim, J.H.; Song, Y.S.; Lee, S.H. Pivotal Roles of Ginsenoside Rg3 in Tumor Apoptosis Through Regulation of Reactive Oxygen Species. Anticancer. Res. 2016, 36, 4647–4654. [Google Scholar] [CrossRef] [Green Version]
  148. Lee, C.K.; Park, K.-K.; Chung, A.-S.; Chung, W.-Y. Ginsenoside Rg3 enhances the chemosensitivity of tumors to cisplatin by reducing the basal level of nuclear factor erythroid 2-related factor 2-mediated heme oxygenase-1/NAD(P)H quinone oxidoreductase-1 and prevents normal tissue damage by scavenging cisplatin-induced intracellular reactive oxygen species. Food Chem. Toxicol. 2012, 50, 2565–2574. [Google Scholar] [CrossRef]
  149. Mileo, A.M.; Miccadei, S. Polyphenols as Modulator of Oxidative Stress in Cancer Disease: New Therapeutic Strategies. Oxidative Med. Cell. Longev. 2015, 2016, 6475624. [Google Scholar] [CrossRef] [Green Version]
  150. Athreya, K.; Xavier, M.F. Antioxidants in the Treatment of Cancer. Nutr. Cancer 2017, 69, 1099–1104. [Google Scholar] [CrossRef]
  151. Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers. N. Engl. J. Med. 1994, 330, 1029–1035. [Google Scholar] [CrossRef] [PubMed]
  152. Rauf, A.; Imran, M.; Butt, M.S.; Nadeem, M.; Peters, D.G.; Mubarak, M.S. Resveratrol as an anti-cancer agent: A review. Crit. Rev. Food Sci. Nutr. 2018, 58, 1428–1447. [Google Scholar] [CrossRef]
  153. Walton, E.L. The dual role of ROS, antioxidants and autophagy in cancer. Biomed. J. 2016, 39, 89–92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Khurana, R.K.; Jain, A.; Jain, A.; Sharma, T.; Singh, B.; Kesharwani, P. Administration of antioxidants in cancer: Debate of the decade. Drug Discov. Today 2018, 23, 763–770. [Google Scholar] [CrossRef] [PubMed]
  155. Yao, K.C.; Komata, T.; Kondo, Y.; Kanzawa, T.; Kondo, S.; Germano, I.M. Molecular response of human glioblastoma multiforme cells to ionizing radiation: Cell cycle arrest, modulation of cyclin-dependent kinase inhibitors, and autophagy. J. Neurosurg. 2003, 98, 378–384. [Google Scholar] [CrossRef]
  156. Tsujimura, T.; Mukubou, H.; Sasaki, R.; Ku, Y. The role of autophagy in the treatment of pancreatic cancer with gemcitabine and ionizing radiation. Int. J. Oncol. 2010, 37, 821–828. [Google Scholar] [CrossRef] [Green Version]
  157. Kamm, A.; Przychodzeń, P.; Kuban-Jankowska, A.; Gammazza, A.M.; Cappello, F.; Daca, A.; Żmijewski, M.A.; Woźniak, M.; Górska–Ponikowska, M. 2-Methoxyestradiol and Its Combination with a Natural Compound, Ferulic Acid, Induces Melanoma Cell Death via Downregulation of Hsp60 and Hsp90. J. Oncol. 2019, 2019, 9293416. [Google Scholar] [CrossRef] [Green Version]
  158. Chen, Y.; McMillan-Ward, E.; Kong, J.; Israels, S.; Gibson, S.B. Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ. 2007, 15, 171–182. [Google Scholar] [CrossRef] [PubMed]
  159. Fan, J.; Ren, D.; Wang, J.; Liu, X.; Zhang, H.; Wu, M.; Yang, G. Bruceine D induces lung cancer cell apoptosis and autophagy via the ROS/MAPK signaling pathway in vitro and in vivo. Cell Death Dis. 2020, 11, 126. [Google Scholar] [CrossRef] [Green Version]
  160. Miki, H.; Uehara, N.; Kimura, A.; Sasaki, T.; Yuri, T.; Yoshizawa, K.; Tsubura, A. Resveratrol induces apoptosis via ROS-triggered autophagy in human colon cancer cells. Int. J. Oncol. 2012, 40, 1020–1028. [Google Scholar] [CrossRef] [Green Version]
  161. Nawrocki, S.T.; Carew, J.S.; Kelly, K.R. Autophagy as a target for cancer therapy: New developments. Cancer Manag. Res. 2012, 4, 357–365. [Google Scholar] [CrossRef] [PubMed]
Life 13 00098 g001 550
Figure 1. The sources and conversion of ROS. The main sources of ROS include mitochondrial electron transport chain (mETC), NOX complex, peroxisome and endoplasmic reticulum (ER). In order to prevent the damage of ROS, cells are equipped with antioxidant defense system, in which superoxide dismutases (SODs), catalases (CATs), glutathione peroxidases (GPXs), peroxiredoxins (PRXs), and thioredoxins (Trxs) are utilized to maintain the redox homeostasis of cells. NOXs, membrane-bound NADPH oxidases. XO, xanthine oxidase. GSH, glutathione. GSSG, glutathione disulfide. GR, glutathione reductase. TRXred, reduced thioredoxin. TRXox, oxidized thioredoxin.
Figure 1. The sources and conversion of ROS. The main sources of ROS include mitochondrial electron transport chain (mETC), NOX complex, peroxisome and endoplasmic reticulum (ER). In order to prevent the damage of ROS, cells are equipped with antioxidant defense system, in which superoxide dismutases (SODs), catalases (CATs), glutathione peroxidases (GPXs), peroxiredoxins (PRXs), and thioredoxins (Trxs) are utilized to maintain the redox homeostasis of cells. NOXs, membrane-bound NADPH oxidases. XO, xanthine oxidase. GSH, glutathione. GSSG, glutathione disulfide. GR, glutathione reductase. TRXred, reduced thioredoxin. TRXox, oxidized thioredoxin.
Life 13 00098 g001
Life 13 00098 g002 550
Figure 2. The process of autophagy. Autophagy is initiated in cells by complex regulatory mechanisms under various stress conditions. Through the joint action of multiple protein complexes, the isolation membrane wraps the cargoes, and gradually extends and closes to form autophagosomes. After maturation, autophagosomes fuse with lysosomes to form autolysosomes to degrade the cargoes, realizing the renewal of materials and maintenance of intracellular homeostasis. ER, endoplasmic reticulum. PAS, phagophore assembly site.
Figure 2. The process of autophagy. Autophagy is initiated in cells by complex regulatory mechanisms under various stress conditions. Through the joint action of multiple protein complexes, the isolation membrane wraps the cargoes, and gradually extends and closes to form autophagosomes. After maturation, autophagosomes fuse with lysosomes to form autolysosomes to degrade the cargoes, realizing the renewal of materials and maintenance of intracellular homeostasis. ER, endoplasmic reticulum. PAS, phagophore assembly site.
Life 13 00098 g002
Life 13 00098 g004 550
Figure 4. Two anticancer strategies based on the regulation of autophagy by ROS. (A) During the treatment with some anticancer drugs, ROS-mediated protective autophagy could be induced in tumor cells, leading to the development of drug resistance. Autophagy inhibitors such as chloroquine (CQ) or antioxidants such as NAC could enhance the sensitivity of tumor cells to anticancer drugs. (B) Some anticancer drugs, such as bruceine D and resveratrol, exerted cytotoxicity in cancer cells by promoting ROS accumulation and ROS-induced autophagic cell death.
Figure 4. Two anticancer strategies based on the regulation of autophagy by ROS. (A) During the treatment with some anticancer drugs, ROS-mediated protective autophagy could be induced in tumor cells, leading to the development of drug resistance. Autophagy inhibitors such as chloroquine (CQ) or antioxidants such as NAC could enhance the sensitivity of tumor cells to anticancer drugs. (B) Some anticancer drugs, such as bruceine D and resveratrol, exerted cytotoxicity in cancer cells by promoting ROS accumulation and ROS-induced autophagic cell death.
Life 13 00098 g004
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

He, J.; Dong, L.; Luo, L.; Wang, K. Redox Regulation of Autophagy in Cancer: Mechanism, Prevention and Therapy. Life 2023, 13, 98. https://doi.org/10.3390/life13010098

AMA Style

He J, Dong L, Luo L, Wang K. Redox Regulation of Autophagy in Cancer: Mechanism, Prevention and Therapy. Life. 2023; 13(1):98. https://doi.org/10.3390/life13010098

Chicago/Turabian Style

He, Jingqiu, Lixia Dong, Li Luo, and Kui Wang. 2023. "Redox Regulation of Autophagy in Cancer: Mechanism, Prevention and Therapy" Life 13, no. 1: 98. https://doi.org/10.3390/life13010098

APA Style

He, J., Dong, L., Luo, L., & Wang, K. (2023). Redox Regulation of Autophagy in Cancer: Mechanism, Prevention and Therapy. Life, 13(1), 98. https://doi.org/10.3390/life13010098

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop