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The Role of Autophagy in Cancer Progression and Drug Resistance

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 59437

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Dr. Steffan T. Nawrocki

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Guest Editor

Department of Medicine, Division of Translational and Regenerative Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA
Interests: autophagy; experimental cancer therapeutics; oncolytic virus therapy; endoplasmic reticular stress; anticancer drug resistance

Special Issue Information

Dear Colleagues,

Autophagy is an evolutionarily conserved lysosome-mediated protein degradation process that functions to turnover organelles and proteins with long half-lives. This role of autophagy suppresses tumor formation via the elimination of defective pre-malignant cells and maintains bioenergetic homeostasis under stress conditions including hypoxia and nutrient deprivation. However, autophagy may also promote cancer progression and drug resistance in established diseases via the generation of alternative sources of energy through nutrient recycling. Despite having diverse mechanisms of action, many frontline anticancer agents ultimately shut down conventional metabolic pathways because of the cellular stress that they impose and, thus, stimulate autophagy. Importantly, pharmacological or genetic inhibition of autophagy significantly enhances the anticancer activity of many different forms of cancer therapeutics. On the basis of these collective findings, it appears that inhibition of autophagy is a promising novel approach with broad applications in cancer therapy. We welcome articles focused on autophagy and its roles in cancer progression and drug resistance.

Dr. Steffan T. Nawrocki
Guest Editor

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Keywords

autophagy
lysosome
protein degradation
drug resistance
cancer
cell survival
cell metabolism
mTOR
combination therapy

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

4 pages, 169 KiB

Open AccessEditorial

Autophagy: New Insights into Its Roles in Cancer Progression and Drug Resistance

by Steffan T. Nawrocki, Wei Wang and Jennifer S. Carew

Cancers 2020, 12(10), 3005; https://doi.org/10.3390/cancers12103005 - 16 Oct 2020

Cited by 8 | Viewed by 2072

Abstract

Autophagy is a mechanism of lysosomal proteolysis that is utilized to degrade damaged organelles, proteins, and other cellular components. Although key studies demonstrate that autophagy functions as a mechanism of tumor suppression via the degradation of defective pre-malignant cells, autophagy can also be used as a mechanism to break down cellular components under stress conditions to generate the required metabolic materials for cell survival. Autophagy has emerged as an important mediator of resistance to radiation, chemotherapy, and targeted agents. This series of articles highlight the role of autophagy in cancer progression and drug resistance and underscores the need for new and more effective agents that target this process. Full article

(This article belongs to the Special Issue The Role of Autophagy in Cancer Progression and Drug Resistance)

Research

Jump to: Editorial, Review

14 pages, 1706 KiB

Open AccessArticle

Targeting Autophagy by MPT0L145, a Highly Potent PIK3C3 Inhibitor, Provides Synergistic Interaction to Targeted or Chemotherapeutic Agents in Cancer Cells

by Chun-Han Chen, Tsung-Han Hsieh, Yu-Chen Lin, Yun-Ru Liu, Jing-Ping Liou and Yun Yen

Cancers 2019, 11(9), 1345; https://doi.org/10.3390/cancers11091345 - 11 Sep 2019

Cited by 16 | Viewed by 3699

Abstract

Anticancer therapies reportedly promote pro-survival autophagy in cancer cells that confers drug resistance, rationalizing the concept to combine autophagy inhibitors to increase their therapeutic potential. We previously identified that MPT0L145 is a PIK3C3/FGFR inhibitor that not only increases autophagosome formation due to fibroblast growth factor receptor (FGFR) inhibition but also perturbs autophagic flux via PIK3C3 inhibition in bladder cancer cells harboring FGFR activation. In this study, we hypothesized that combined-use of MPT0L145 with agents that induce pro-survival autophagy may provide synthetic lethality in cancer cells without FGFR activation. The results showed that MPT0L145 synergistically sensitizes anticancer effects of gefitinib and gemcitabine in non-small cell lung cancer A549 cells and pancreatic cancer PANC-1 cells, respectively. Mechanistically, drug combination increased incomplete autophagy due to impaired PIK3C3 function by MPT0L145 as evidenced by p62 accumulation and no additional apoptotic cell death was observed. Meanwhile, drug combination perturbed survival pathways and increased vacuolization and ROS production in cancer cells. In conclusion, the data suggest that halting pro-survival autophagy by targeting PIK3C3 with MPT0L145 significantly sensitizes cancer cells to targeted or chemotherapeutic agents, fostering rational combination strategies for cancer therapy in the future. Full article

(This article belongs to the Special Issue The Role of Autophagy in Cancer Progression and Drug Resistance)

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18 pages, 8249 KiB

Open AccessArticle

Cannabidiol Overcomes Oxaliplatin Resistance by Enhancing NOS3- and SOD2-Induced Autophagy in Human Colorectal Cancer Cells

by Soyeon Jeong, Bu Gyeom Kim, Dae Yeong Kim, Bo Ram Kim, Jung Lim Kim, Seong Hye Park, Yoo Jin Na, Min Jee Jo, Hye Kyeong Yun, Yoon A. Jeong, Hong Jun Kim, Sun Il Lee, Han Do Kim, Dae Hyun Kim, Sang Cheul Oh and Dae-Hee Lee

Cancers 2019, 11(6), 781; https://doi.org/10.3390/cancers11060781 - 5 Jun 2019

Cited by 66 | Viewed by 8135

Abstract

Although oxaliplatin is an effective chemotherapeutic drug for colorectal cancer (CRC) treatment, patients often develop resistance to it. Therefore, a new strategy for CRC treatment is needed. The purpose of this study was to determine the effect of cannabidiol (CBD), one of the components of the cannabis plant, in overcoming oxaliplatin resistance in CRC cells. We established oxaliplatin-resistant cell lines, DLD-1 R and colo205 R, in CRC DLD-1 and colo205 cells. Autophagic cell death was induced when oxaliplatin-resistant cells were treated with both oxaliplatin and CBD. Additionally, phosphorylation of nitric oxide synthase 3 (NOS3) was increased in oxaliplatin-resistant cells compared to that in parent cells. Combined treatment with oxaliplatin and CBD reduced phospho-NOS3 levels and nitric oxide (NO) production and resulted in the production of reactive oxygen species (ROS) by reducing the levels of superoxide dismutase 2, an antioxidant present in the mitochondria, causing mitochondrial dysfunction. Taken together, these results suggest that elevated phosphorylation of NOS3 is essential for oxaliplatin resistance. The combination of oxaliplatin and CBD decreased NOS3 phosphorylation, which resulted in autophagy, by inducing the overproduction of ROS through mitochondrial dysfunction, thus overcoming oxaliplatin resistance. Full article

(This article belongs to the Special Issue The Role of Autophagy in Cancer Progression and Drug Resistance)

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Graphical abstract

11 pages, 1507 KiB

Open AccessArticle

Immunohistochemical Expression of Autophagy-Related Proteins in Advanced Tubular Gastric Adenocarcinomas and Its Implications

by Antonio Ieni, Roberta Cardia, Giuseppe Giuffrè, Luciana Rigoli, Rosario Alberto Caruso and Giovanni Tuccari

Cancers 2019, 11(3), 389; https://doi.org/10.3390/cancers11030389 - 19 Mar 2019

Cited by 17 | Viewed by 3813

Abstract

In neoplastic conditions, autophagy may act as a tumor suppressor avoiding the accumulation of damaged proteins and organelles or as a mechanism of cell survival promoting the tumor growth. Although ultrastructural analysis has been considered the traditional method to identify autophagy, some proteins such as microtubule-associated protein 1 light chain 3 (LC3A/B), Beclin-1 and activating molecule in Beclin-1-regulated autophagy protein-1 (AMBRA-1) may be considered as markers of autophagy-assisted cancerogenesis. Herein, we analyzed a cohort of advanced tubular gastric adenocarcinomas by the abovementioned immunohistochemical antisera; through immunohistochemistry, autophagy (A-IHC) is diagnosed when at least two out of the three proteins are positive in the samples. Immunostaining for LC3A/B, Beclin-1, and AMBRA-1 was exclusively found in neoplastic elements, but not in surrounding stromal cells. In detail, LC3A/B and Beclin 1 were expressed both in the cytoplasm and in the nucleus of the cancer cells, while AMBRA-1 was preferentially localized in the nucleus, mainly in high grade cases. LC3A/B, Beclin 1, and AMBRA-1 expression were positive in 18 (56.2%), 17 (53.1%), and 12 (37.5%) cases, respectively. The sensibility and specificity of LC3A/B and Beclin-1 ranged from 81.25% to 93.75%, with high efficiency (90.63%) for Beclin-1. Moreover, the ultrastructural autophagic index (AI) was also available in all cases. All high-grade cases documented a Ki-67 labelling index (LI) ≥ 30%, even if three low-grade cases revealed a high Ki-67 value; p53 positivity was encountered in 21/32 (65.62%) of cases, independently of the tumor grade. A statistically significant correlation among A-IHC and clinicopathological parameters such as grade, stage, clinical course, Ki-67 LI and AI was revealed. Univariate analysis documented a significant p-value for the same autophagic variables. Additionally, multivariate survival analysis identified the grade, AI and A-IHC as independent significant variables. Finally, the overall survival curves of all cases of gastric tubular adenocarcinoma were greatly dependent on A-IHC. Therefore, we suggest that autophagic-related proteins might be considered promising predictive prognostic factors of advanced gastric cancer. Further investigations may be required to determine whether new targeted therapies should be addressed to autophagy-related proteins. Full article

(This article belongs to the Special Issue The Role of Autophagy in Cancer Progression and Drug Resistance)

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Review

Jump to: Editorial, Research

30 pages, 795 KiB

Open AccessReview

Molecular Determinants of Cancer Therapy Resistance to HDAC Inhibitor-Induced Autophagy

by Maria Mrakovcic and Leopold F. Fröhlich

Cancers 2020, 12(1), 109; https://doi.org/10.3390/cancers12010109 - 31 Dec 2019

Cited by 31 | Viewed by 5763

Abstract

Histone deacetylation inhibitors (HDACi) offer high potential for future cancer therapy as they can re-establish the expression of epigenetically silenced cell death programs. HDACi-induced autophagy offers the possibility to counteract the frequently present apoptosis-resistance as well as stress conditions of cancer cells. Opposed to the function of apoptosis and necrosis however, autophagy activated in cancer cells can engage in a tumor-suppressive or tumor-promoting manner depending on mostly unclarified factors. As a physiological adaption to apoptosis resistance in early phases of tumorigenesis, autophagy seems to resume a tumorsuppressive role that confines tumor necrosis and inflammation or even induces cell death in malignant cells. During later stages of tumor development, chemotherapeutic drug-induced autophagy seems to be reprogrammed by the cancer cell to prevent its elimination and support tumor progression. Consistently, HDACi-mediated activation of autophagy seems to exert a protective function that prevents the induction of apoptotic or necrotic cell death in cancer cells. Thus, resistance to HDACi-induced cell death is often encountered in various types of cancer as well. The current review highlights the different mechanisms of HDACi-elicited autophagy and corresponding possible molecular determinants of therapeutic resistance in cancer. Full article

(This article belongs to the Special Issue The Role of Autophagy in Cancer Progression and Drug Resistance)

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49 pages, 3734 KiB

Open AccessReview

Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer

by Cally J. Ho and Sharon M. Gorski

Cancers 2019, 11(11), 1775; https://doi.org/10.3390/cancers11111775 - 11 Nov 2019

Cited by 68 | Viewed by 9926

Abstract

Despite advances in diagnostic tools and therapeutic options, treatment resistance remains a challenge for many cancer patients. Recent studies have found evidence that autophagy, a cellular pathway that delivers cytoplasmic components to lysosomes for degradation and recycling, contributes to treatment resistance in different cancer types. A role for autophagy in resistance to chemotherapies and targeted therapies has been described based largely on associations with various signaling pathways, including MAPK and PI3K/AKT signaling. However, our current understanding of the molecular mechanisms underlying the role of autophagy in facilitating treatment resistance remains limited. Here we provide a comprehensive summary of the evidence linking autophagy to major signaling pathways in the context of treatment resistance and tumor progression, and then highlight recently emerged molecular mechanisms underlying autophagy and the p62/KEAP1/NRF2 and FOXO3A/PUMA axes in chemoresistance. Full article

(This article belongs to the Special Issue The Role of Autophagy in Cancer Progression and Drug Resistance)

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17 pages, 6138 KiB

Open AccessReview

Roles for Autophagy in Esophageal Carcinogenesis: Implications for Improving Patient Outcomes

by Reshu Saxena, Alena Klochkova, Mary Grace Murray, Mohammad Faujul Kabir, Safiyah Samad, Tyler Beccari, Julie Gang, Kishan Patel, Kathryn E. Hamilton and Kelly A. Whelan

Cancers 2019, 11(11), 1697; https://doi.org/10.3390/cancers11111697 - 31 Oct 2019

Cited by 22 | Viewed by 4921

Abstract

Esophageal cancer is among the most aggressive forms of human malignancy with five-year survival rates of <20%. Autophagy is an evolutionarily conserved catabolic process that degrades and recycles damaged organelles and misfolded proteins to maintain cellular homeostasis. While alterations in autophagy have been associated with carcinogenesis across tissues, cell type- and context-dependent roles for autophagy have been reported. Herein, we review the current knowledge related to autophagy in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), the two most common subtypes of esophageal malignancy. We explore roles for autophagy in the development and progression of ESCC and EAC. We then continue to discuss molecular markers of autophagy as they relate to esophageal patient outcomes. Finally, we summarize current literature examining roles for autophagy in ESCC and EAC response to therapy and discuss considerations for the potential use of autophagy inhibitors as experimental therapeutics that may improve patient outcomes in esophageal cancer. Full article

(This article belongs to the Special Issue The Role of Autophagy in Cancer Progression and Drug Resistance)

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47 pages, 9681 KiB

Open AccessEditor’s ChoiceReview

Targeting Autophagy for Cancer Treatment and Tumor Chemosensitization

by Marta Pérez-Hernández, Alain Arias, David Martínez-García, Ricardo Pérez-Tomás, Roberto Quesada and Vanessa Soto-Cerrato

Cancers 2019, 11(10), 1599; https://doi.org/10.3390/cancers11101599 - 19 Oct 2019

Cited by 111 | Viewed by 7671

Abstract

Autophagy is a tightly regulated catabolic process that facilitates nutrient recycling from damaged organelles and other cellular components through lysosomal degradation. Deregulation of this process has been associated with the development of several pathophysiological processes, such as cancer and neurodegenerative diseases. In cancer, autophagy has opposing roles, being either cytoprotective or cytotoxic. Thus, deciphering the role of autophagy in each tumor context is crucial. Moreover, autophagy has been shown to contribute to chemoresistance in some patients. In this regard, autophagy modulation has recently emerged as a promising therapeutic strategy for the treatment and chemosensitization of tumors, and has already demonstrated positive clinical results in patients. In this review, the dual role of autophagy during carcinogenesis is discussed and current therapeutic strategies aimed at targeting autophagy for the treatment of cancer, both under preclinical and clinical development, are presented. The use of autophagy modulators in combination therapies, in order to overcome drug resistance during cancer treatment, is also discussed as well as the potential challenges and limitations for the use of these novel therapeutic strategies in the clinic. Full article

(This article belongs to the Special Issue The Role of Autophagy in Cancer Progression and Drug Resistance)

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18 pages, 1014 KiB

Open AccessReview

Involvement of Actin in Autophagy and Autophagy-Dependent Multidrug Resistance in Cancer

by Magdalena Izdebska, Wioletta Zielińska, Marta Hałas-Wiśniewska and Alina Grzanka

Cancers 2019, 11(8), 1209; https://doi.org/10.3390/cancers11081209 - 20 Aug 2019

Cited by 17 | Viewed by 5498

Abstract

Currently, autophagy in the context of cancer progression arouses a lot of controversy. It is connected with the possibility of switching the nature of this process from cytotoxic to cytoprotective and vice versa depending on the treatment. At the same time, autophagy of cytoprotective character may be one of the factors determining multidrug resistance, as intensification of the process is observed in patients with poorer prognosis. The exact mechanism of this relationship is not yet fully understood; however, it is suggested that one of the elements of the puzzle may be a cytoskeleton. In the latest literature reports, more and more attention is paid to the involvement of actin in the autophagy. The role of this protein is linked to the formation of autophagosomes, which are necessary element of the process. However, based on the proven effectiveness of manipulation of the actin pool, it seems to be an attractive alternative in breaking autophagy-dependent multidrug resistance in cancer. Full article

(This article belongs to the Special Issue The Role of Autophagy in Cancer Progression and Drug Resistance)

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17 pages, 2417 KiB

Open AccessReview

Targeting ATG4 in Cancer Therapy

by Yuanyuan Fu, Zhiying Huang, Liang Hong, Jia-Hong Lu, Du Feng, Xiao-Ming Yin and Min Li

Cancers 2019, 11(5), 649; https://doi.org/10.3390/cancers11050649 - 10 May 2019

Cited by 35 | Viewed by 7071

Abstract

Autophagy is a lysosome-mediated degradation pathway that enables the degradation and recycling of cytoplasmic components to sustain metabolic homoeostasis. Recently, autophagy has been reported to have an astonishing number of connections to cancer, as tumor cells require proficient autophagy in response to metabolic and therapeutic stresses to sustain cell proliferation. Autophagy-related gene 4 (ATG4) is essential for autophagy by affecting autophagosome formation through processing full-length microtubule-associated protein 1A/1B-light chain 3 (pro-LC3) and lipidated LC3. An increasing amount of evidence suggests that ATG4B expression is elevated in certain types of cancer, implying that ATG4B is a potential anticancer target. In this review, we address the central roles of ATG4B in the autophagy machinery and in targeted cancer therapy. Specifically, we discuss how pharmacologically inhibiting ATG4B can benefit cancer therapies. Full article

(This article belongs to the Special Issue The Role of Autophagy in Cancer Progression and Drug Resistance)

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