Cells

Editorial

5 pages, 210 KiB

Open AccessEditorial

Exploring the Complex Link between Autophagy, Regulated Cell Death, and Cell Fate Pathways in Cancer Pathogenesis and Therapy

by Mohammad Amin Moosavi and Mojgan Djavaheri-Mergny

Cells 2023, 12(3), 498; https://doi.org/10.3390/cells12030498 - 3 Feb 2023

Viewed by 1842

Abstract

Autophagy is a catabolic lysosomal-dependent pathway involved in the degradation of cellular materials, supplying precursor compounds and energy for macromolecule synthesis and metabolic needs [...] Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

Research

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16 pages, 6995 KiB

Open AccessArticle

Identification of Small Molecules Inhibiting Cardiomyocyte Necrosis and Apoptosis by Autophagy Induction and Metabolism Reprogramming

by Dawei Liu, Félix Peyre, Yahir Alberto Loissell-Baltazar, Delphine Courilleau, Sandra Lacas-Gervais, Valérie Nicolas, Eric Jacquet, Svetlana Dokudovskaya, Frédéric Taran, Jean-Christophe Cintrat and Catherine Brenner

Cells 2022, 11(3), 474; https://doi.org/10.3390/cells11030474 - 29 Jan 2022

Cited by 2 | Viewed by 3041

Abstract

Improvement of anticancer treatments is associated with increased survival of cancer patients at risk of cardiac disease. Therefore, there is an urgent need for new therapeutic molecules capable of preventing acute and long-term cardiotoxicity. Here, using commercial and home-made chemolibraries, we performed a [...] Read more.

Improvement of anticancer treatments is associated with increased survival of cancer patients at risk of cardiac disease. Therefore, there is an urgent need for new therapeutic molecules capable of preventing acute and long-term cardiotoxicity. Here, using commercial and home-made chemolibraries, we performed a robust phenotypic high-throughput screening in rat cardiomyoblast cell line H9c2, searching for small molecules capable of inhibiting cell death. A screen of 1600 compounds identified six molecules effective in preventing necrosis and apoptosis induced by H₂O₂ and camptothecin in H9c2 cells and in rat neonatal ventricular myocytes. In cells treated with these molecules, we systematically evaluated the expression of BCL-2 family members, autophagy progression, mitochondrial network structure, regulation of mitochondrial fusion/fission, reactive oxygen species, and ATP production. We found that these compounds affect autophagy induction to prevent cardiac cell death and can be promising cardioprotective drugs during chemotherapy. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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18 pages, 2709 KiB

Open AccessFeature PaperArticle

TRAIL Triggers CRAC-Dependent Calcium Influx and Apoptosis through the Recruitment of Autophagy Proteins to Death-Inducing Signaling Complex

by Kelly Airiau, Pierre Vacher, Olivier Micheau, Valerie Prouzet-Mauleon, Guido Kroemer, Mohammad Amin Moosavi and Mojgan Djavaheri-Mergny

Cells 2022, 11(1), 57; https://doi.org/10.3390/cells11010057 - 25 Dec 2021

Cited by 5 | Viewed by 3992

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills various cancer cell types, but also leads to the activation of signaling pathways that favor resistance to cell death. Here, we investigated the as yet unknown roles of calcium signaling and autophagy regulatory proteins during [...] Read more.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills various cancer cell types, but also leads to the activation of signaling pathways that favor resistance to cell death. Here, we investigated the as yet unknown roles of calcium signaling and autophagy regulatory proteins during TRAIL-induced cell death in leukemia cells. Taking advantage of the Gene Expression Profiling Interactive Analysis (GEPIA) project, we first found that leukemia patients present a unique TRAIL receptor gene expression pattern that may reflect their resistance to TRAIL. The exposure of NB4 acute promyelocytic leukemia cells to TRAIL induces intracellular Ca²⁺ influx through a calcium release-activated channel (CRAC)-dependent mechanism, leading to an anti-apoptotic response. Mechanistically, we showed that upon TRAIL treatment, two autophagy proteins, ATG7 and p62/SQSTM1, are recruited to the death-inducing signaling complex (DISC) and are essential for TRAIL-induced Ca²⁺ influx and cell death. Importantly, the treatment of NB4 cells with all-trans retinoic acid (ATRA) led to the upregulation of p62/SQSTM1 and caspase-8 and, when added prior to TRAIL stimulation, significantly enhanced DISC formation and the apoptosis induced by TRAIL. In addition to uncovering new pleiotropic roles for autophagy proteins in controlling the calcium response and apoptosis triggered by TRAIL, our results point to novel therapeutic strategies for sensitizing leukemia cells to TRAIL. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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19 pages, 3346 KiB

Open AccessArticle

Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid

by Faten Merhi, Karla Alvarez-Valadez, Jenifer Trepiana, Claire Lescoat, Alexis Groppi, Jean-William Dupuy, Pierre Soubeyran, Guido Kroemer, Pierre Vacher and Mojgan Djavaheri-Mergny

Cells 2021, 10(12), 3364; https://doi.org/10.3390/cells10123364 - 30 Nov 2021

Cited by 9 | Viewed by 3006

Abstract

Calcium ions (Ca²⁺) play important and diverse roles in the regulation of autophagy, cell death and differentiation. Here, we investigated the impact of Ca²⁺ in regulating acute promyelocytic leukemia (APL) cell fate in response to the anti-cancer agent all-trans retinoic [...] Read more.

Calcium ions (Ca²⁺) play important and diverse roles in the regulation of autophagy, cell death and differentiation. Here, we investigated the impact of Ca²⁺ in regulating acute promyelocytic leukemia (APL) cell fate in response to the anti-cancer agent all-trans retinoic acid (ATRA). We observed that ATRA promotes calcium entry through store-operated calcium (SOC) channels into acute promyelocytic leukemia (APL) cells. This response is associated with changes in the expression profiles of ORAI1 and STIM1, two proteins involved in SOC channels activation, as well as with a significant upregulation of several key proteins associated to calcium signaling. Moreover, ATRA treatment of APL cells led to a significant activation of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) and its downstream effector AMP-activated protein kinase (AMPK), linking Ca²⁺ signaling to autophagy. Pharmacological inhibition of SOC channels and CAMKK2 enhanced ATRA-induced cell differentiation and death. Altogether, our results unravel an ATRA-elicited signaling pathway that involves SOC channels/CAMKK2 activation, induction of autophagy, inhibition of cellular differentiation and suppression of cell death. We suggest that SOC channels and CAMKK2 may constitute novel drug targets for potentiating the anti-cancer effect of ATRA in APL patients. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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15 pages, 4628 KiB

Open AccessArticle

Chaperone-Mediated Autophagy Markers LAMP2A and HSPA8 in Advanced Non-Small Cell Lung Cancer after Neoadjuvant Therapy

by Tereza Losmanova, Philipp Zens, Amina Scherz, Ralph A. Schmid, Mario P. Tschan and Sabina Berezowska

Cells 2021, 10(10), 2731; https://doi.org/10.3390/cells10102731 - 13 Oct 2021

Cited by 6 | Viewed by 3569

Abstract

In recent years autophagy has attracted the attention of researchers from many medical fields, including cancer research, and certain anti-macroautophagy drugs in combination with cytotoxic or targeted therapies have entered clinical trials. In the present study, we focused on a less explored subtype [...] Read more.

In recent years autophagy has attracted the attention of researchers from many medical fields, including cancer research, and certain anti-macroautophagy drugs in combination with cytotoxic or targeted therapies have entered clinical trials. In the present study, we focused on a less explored subtype of autophagy, i.e., chaperone-mediated autophagy (CMA), with the key proteins LAMP2A and HSPA8 (HSC70), and their immunohistochemical evaluation with previously extensively validated antibodies. We were interested in whether the marker expression is influenced by the antecedent therapy, and its correlation with survival on a cohort of patients with non-small cell lung cancer (NSCLC) after neoadjuvant therapy and matched primary resected tumors. In concordance with our previous study, we did not find any intratumoral heterogeneity, nor correlation between the two parameters, nor correlation between the markers and any included pathological parameters. Surprisingly, the expression of both markers was also independent to tumor response or administered neoadjuvant treatment. In the survival analysis, the results were only significant for LAMP2A, where higher levels were associated with longer 5-year overall survival and disease-free survival for the mixed group of adenocarcinomas and squamous cell carcinomas (p < 0.0001 and p = 0.0019 respectively) as well as the squamous cell carcinoma subgroup (p = 0.0001 and p = 0.0001 respectively). LAMP2A was also an independent prognostic marker in univariate and multivariate analysis. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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12 pages, 2119 KiB

Open AccessFeature PaperArticle

Acute Valproate Exposure Induces Mitochondrial Biogenesis and Autophagy with FOXO3a Modulation in SH-SY5Y Cells

by Eun-Hye Jang, Jung-Ho Lee and Soon-Ae Kim

Cells 2021, 10(10), 2522; https://doi.org/10.3390/cells10102522 - 23 Sep 2021

Cited by 8 | Viewed by 3045

Abstract

Valproic acid (VPA) is an antiepileptic drug found to induce mitochondrial dysfunction and autophagy in cancer cell lines. We treated the SH-SY5Y cell line with various concentrations of VPA (1, 5, and 10 mM). The treatment decreased cell viability, ATP production, and mitochondrial [...] Read more.

Valproic acid (VPA) is an antiepileptic drug found to induce mitochondrial dysfunction and autophagy in cancer cell lines. We treated the SH-SY5Y cell line with various concentrations of VPA (1, 5, and 10 mM). The treatment decreased cell viability, ATP production, and mitochondrial membrane potential and increased reactive oxygen species production. In addition, the mitochondrial DNA copy number increased after VPA treatment in a dose-dependent manner. Western blotting showed that the levels of mitochondrial biogenesis-related proteins (PGC-1α, TFAM, and COX4) increased, though estrogen-related receptor expression decreased after VPA treatment. Further, VPA treatment increased the total and acetylated FOXO3a protein levels. Although SIRT1 expression was decreased, SIRT3 expression was increased, which regulated FOXO3 acetylation in the mitochondria. Furthermore, VPA treatment induced autophagy via increased LC3-II levels and decreased p62 expression and mTOR phosphorylation. We suggest that VPA treatment induces mitochondrial biogenesis and autophagy via changes in FOXO3a expression and posttranslational modification in the SH-SY5Y cell line. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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20 pages, 2522 KiB

Open AccessFeature PaperArticle

Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion

by Alexandra Nguyen, Melanie Dzulko, Janine Murr, Yun Yen, Günter Schneider and Oliver H. Krämer

Cells 2021, 10(10), 2520; https://doi.org/10.3390/cells10102520 - 23 Sep 2021

Cited by 6 | Viewed by 3698

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a dismal prognosis. Here, we show how an inhibition of de novo dNTP synthesis by the ribonucleotide reductase (RNR) inhibitor hydroxyurea and an inhibition of epigenetic modifiers of the histone deacetylase (HDAC) family [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a dismal prognosis. Here, we show how an inhibition of de novo dNTP synthesis by the ribonucleotide reductase (RNR) inhibitor hydroxyurea and an inhibition of epigenetic modifiers of the histone deacetylase (HDAC) family affect short-term cultured primary murine PDAC cells. We used clinically relevant doses of hydroxyurea and the class 1 HDAC inhibitor entinostat. We analyzed the cells by flow cytometry and immunoblot. Regarding the induction of apoptosis and DNA replication stress, hydroxyurea and the novel RNR inhibitor COH29 are superior to the topoisomerase-1 inhibitor irinotecan which is used to treat PDAC. Entinostat promotes the induction of DNA replication stress by hydroxyurea. This is associated with an increase in the PP2A subunit PR130/PPP2R3A and a reduction of the ribonucleotide reductase subunit RRM2 and the DNA repair protein RAD51. We further show that class 1 HDAC activity promotes the hydroxyurea-induced activation of the checkpoint kinase ataxia-telangiectasia mutated (ATM). Unlike in other cell systems, ATM is pro-apoptotic in hydroxyurea-treated murine PDAC cells. These data reveal novel insights into a cytotoxic, ATM-regulated, and HDAC-dependent replication stress program in PDAC cells. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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17 pages, 4083 KiB

Open AccessCommunication

Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis

by Pawan Sharma, Javad Alizadeh, Maya Juarez, Afshin Samali, Andrew J. Halayko, Nicholas J. Kenyon, Saeid Ghavami and Amir A. Zeki

Cells 2021, 10(7), 1642; https://doi.org/10.3390/cells10071642 - 30 Jun 2021

Cited by 51 | Viewed by 4894

Abstract

Autophagy, apoptosis, and the unfolded protein response (UPR) are fundamental biological processes essential for manifold cellular functions in health and disease. Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disorder associated with aging that has limited therapies, reflecting our incomplete understanding. [...] Read more.

Autophagy, apoptosis, and the unfolded protein response (UPR) are fundamental biological processes essential for manifold cellular functions in health and disease. Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disorder associated with aging that has limited therapies, reflecting our incomplete understanding. We conducted an observational study linking molecular markers of cell stress response pathways (UPR: BiP, XBP1; apoptosis: cleaved caspase-3; autophagy: LC3β) in lung tissues from IPF patients and correlated the expression of these protein markers to each subject’s lung function measures. We hypothesized that changes in lung tissue expression of apoptosis, autophagy, and UPR markers correlate with lung function deficits in IPF. The cell stress markers BiP, XBP1, LC3β puncta, and cleaved caspase-3 were found to be elevated in IPF lungs compared to non-IPF lungs, and, further, BiP and cleaved caspase-3 co-localized in IPF lungs. Considering lung function independently, we observed that increased XBP1, BiP, and cleaved caspase-3 were each associated with reduced lung function (FEV1, FVC, TLC, RV). However, increased lung tissue expression of LC3β puncta was significantly associated with increased diffusion capacity (DLCO), an indicator of alveolar–capillary membrane function. Similarly, the co-localization of UPR (XBP1, BiP) and autophagy (LC3β puncta) markers was positively correlated with increased lung function (FEV1, FVC, TLC, DLCO). However, the presence of LC3β puncta can indicate either autophagy flux inhibition or activation. While the nature of our observational cross-sectional study design does not allow conclusions regarding causal links between increased expression of these cell stress markers, lung fibrosis, and lung function decline, it does provide some insights that are hypothesis-generating and suggests that within the milieu of active UPR, changes in autophagy flux may play an important role in determining lung function. Further research is necessary to investigate the mechanisms linking UPR and autophagy in IPF and how an imbalance in these cell stress pathways can lead to progressive fibrosis and loss of lung function. We conclude by presenting five testable hypotheses that build on the research presented here. Such an understanding could eventually lead to the development of much-needed therapies for IPF. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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24 pages, 4599 KiB

Open AccessArticle

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

by Sanaz Dastghaib, Shahla Shojaei, Zohreh Mostafavi-Pour, Pawan Sharma, John B. Patterson, Afshin Samali, Pooneh Mokarram and Saeid Ghavami

Cells 2020, 9(11), 2339; https://doi.org/10.3390/cells9112339 - 22 Oct 2020

Cited by 51 | Viewed by 5975 | Correction

Abstract

Glioblastoma (GBM) is the most prevalent malignant primary brain tumor with a very poor survival rate. Temozolomide (TMZ) is the common chemotherapeutic agent used for GBM treatment. We recently demonstrated that simvastatin (Simva) increases TMZ-induced apoptosis via the inhibition of autophagic flux in [...] Read more.

Glioblastoma (GBM) is the most prevalent malignant primary brain tumor with a very poor survival rate. Temozolomide (TMZ) is the common chemotherapeutic agent used for GBM treatment. We recently demonstrated that simvastatin (Simva) increases TMZ-induced apoptosis via the inhibition of autophagic flux in GBM cells. Considering the role of the unfolded protein response (UPR) pathway in the regulation of autophagy, we investigated the involvement of UPR in Simva–TMZ-induced cell death by utilizing highly selective IRE1 RNase activity inhibitor MKC8866, PERK inhibitor GSK-2606414 (PERKi), and eIF2α inhibitor salubrinal. Simva–TMZ treatment decreased the viability of GBM cells and significantly increased apoptotic cell death when compared to TMZ or Simva alone. Simva–TMZ induced both UPR, as determined by an increase in GRP78, XBP splicing, eukaryote initiation factor 2α (eIF2α) phosphorylation, and inhibited autophagic flux (accumulation of LC3β-II and inhibition of p62 degradation). IRE1 RNase inhibition did not affect Simva–TMZ-induced cell death, but it significantly induced p62 degradation and increased the microtubule-associated proteins light chain 3 (LC3)β-II/LC3β-I ratio in U87 cells, while salubrinal did not affect the Simva–TMZ induced cytotoxicity of GBM cells. In contrast, protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibition significantly increased Simva–TMZ-induced cell death in U87 cells. Interestingly, whereas PERK inhibition induced p62 accumulation in both GBM cell lines, it differentially affected the LC3β-II/LC3β-I ratio in U87 (decrease) and U251 (increase) cells. Simvastatin sensitizes GBM cells to TMZ-induced cell death via a mechanism that involves autophagy and UPR pathways. More specifically, our results imply that the IRE1 and PERK signaling arms of the UPR regulate Simva–TMZ-mediated autophagy flux inhibition in U251 and U87 GBM cells. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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Review

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19 pages, 19995 KiB

Open AccessReview

Autophagy Contributes to Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Tumors

by Gabriela Reyes-Castellanos, Nadine Abdel Hadi and Alice Carrier

Cells 2022, 11(3), 426; https://doi.org/10.3390/cells11030426 - 26 Jan 2022

Cited by 20 | Viewed by 4738

Abstract

Metabolic reprogramming is a feature of cancers for which recent research has been particularly active, providing numerous insights into the mechanisms involved. It occurs across the entire cancer process, from development to resistance to therapies. Established tumors exhibit dependencies for metabolic pathways, constituting [...] Read more.

Metabolic reprogramming is a feature of cancers for which recent research has been particularly active, providing numerous insights into the mechanisms involved. It occurs across the entire cancer process, from development to resistance to therapies. Established tumors exhibit dependencies for metabolic pathways, constituting vulnerabilities that can be targeted in the clinic. This knowledge is of particular importance for cancers that are refractory to any therapeutic approach, such as Pancreatic Ductal Adenocarcinoma (PDAC). One of the metabolic pathways dysregulated in PDAC is autophagy, a survival process that feeds the tumor with recycled intracellular components, through both cell-autonomous (in tumor cells) and nonautonomous (from the local and distant environment) mechanisms. Autophagy is elevated in established PDAC tumors, contributing to aberrant proliferation and growth even in a nutrient-poor context. Critical elements link autophagy to PDAC including genetic alterations, mitochondrial metabolism, the tumor microenvironment (TME), and the immune system. Moreover, high autophagic activity in PDAC is markedly related to resistance to current therapies. In this context, combining autophagy inhibition with standard chemotherapy, and/or drugs targeting other vulnerabilities such as metabolic pathways or the immune response, is an ongoing clinical strategy for which there is still much to do through translational and multidisciplinary research. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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24 pages, 2525 KiB

Open AccessReview

Cardiac Glycosides as Autophagy Modulators

by Jan Škubník, Vladimíra Svobodová Pavlíčková, Jana Psotová and Silvie Rimpelová

Cells 2021, 10(12), 3341; https://doi.org/10.3390/cells10123341 - 28 Nov 2021

Cited by 15 | Viewed by 4108

Abstract

Drug repositioning is one of the leading strategies in modern therapeutic research. Instead of searching for completely novel substances and demanding studies of their biological effects, much attention has been paid to the evaluation of commonly used drugs, which could be utilized for [...] Read more.

Drug repositioning is one of the leading strategies in modern therapeutic research. Instead of searching for completely novel substances and demanding studies of their biological effects, much attention has been paid to the evaluation of commonly used drugs, which could be utilized for more distinct indications than they have been approved for. Since treatment approaches for cancer, one of the most extensively studied diseases, have still been very limited, great effort has been made to find or repurpose novel anticancer therapeutics. One of these are cardiac glycosides, substances commonly used to treat congestive heart failure or various arrhythmias. Recently, the antitumor properties of cardiac glycosides have been discovered and, therefore, these compounds are being considered for anticancer therapy. Their mechanism of antitumor action seems to be rather complex and not fully uncovered yet, however, autophagy has been confirmed to play a key role in this process. In this review article, we report on the up-to-date knowledge of the anticancer activity of cardiac glycosides with special attention paid to autophagy induction, the molecular mechanisms of this process, and the potential employment of this phenomenon in clinical practice. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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22 pages, 1497 KiB

Open AccessReview

Ferroptosis: Cancer Stem Cells Rely on Iron until “to Die for” It

by Emma Cosialls, Rima El Hage, Leïla Dos Santos, Chang Gong, Maryam Mehrpour and Ahmed Hamaï

Cells 2021, 10(11), 2981; https://doi.org/10.3390/cells10112981 - 2 Nov 2021

Cited by 52 | Viewed by 6542

Abstract

Cancer stem cells (CSCs) are a distinct subpopulation of tumor cells with stem cell-like features. Able to initiate and sustain tumor growth and mostly resistant to anti-cancer therapies, they are thought responsible for tumor recurrence and metastasis. Recent accumulated evidence supports that iron [...] Read more.

Cancer stem cells (CSCs) are a distinct subpopulation of tumor cells with stem cell-like features. Able to initiate and sustain tumor growth and mostly resistant to anti-cancer therapies, they are thought responsible for tumor recurrence and metastasis. Recent accumulated evidence supports that iron metabolism with the recent discovery of ferroptosis constitutes a promising new lead in the field of anti-CSC therapeutic strategies. Indeed, iron uptake, efflux, storage and regulation pathways are all over-engaged in the tumor microenvironment suggesting that the reprogramming of iron metabolism is a crucial occurrence in tumor cell survival. In particular, recent studies have highlighted the importance of iron metabolism in the maintenance of CSCs. Furthermore, the high concentration of iron found in CSCs, as compared to non-CSCs, underlines their iron addiction. In line with this, if iron is an essential macronutrient that is nevertheless highly reactive, it represents their Achilles’ heel by inducing ferroptosis cell death and therefore providing opportunities to target CSCs. In this review, we first summarize our current understanding of iron metabolism and its regulation in CSCs. Then, we provide an overview of the current knowledge of ferroptosis and discuss the role of autophagy in the (regulation of) ferroptotic pathways. Finally, we discuss the potential therapeutic strategies that could be used for inducing ferroptosis in CSCs to treat cancer. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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26 pages, 3236 KiB

Open AccessReview

Autophagy in Tumor Immunity and Viral-Based Immunotherapeutic Approaches in Cancer

by Ali Zahedi-Amiri, Kyle Malone, Shawn T. Beug, Tommy Alain and Behzad Yeganeh

Cells 2021, 10(10), 2672; https://doi.org/10.3390/cells10102672 - 6 Oct 2021

Cited by 7 | Viewed by 3923

Abstract

Autophagy is a fundamental catabolic process essential for the maintenance of cellular and tissue homeostasis, as well as directly contributing to the control of invading pathogens. Unsurprisingly, this process becomes critical in supporting cellular dysregulation that occurs in cancer, particularly the tumor microenvironments [...] Read more.

Autophagy is a fundamental catabolic process essential for the maintenance of cellular and tissue homeostasis, as well as directly contributing to the control of invading pathogens. Unsurprisingly, this process becomes critical in supporting cellular dysregulation that occurs in cancer, particularly the tumor microenvironments and their immune cell infiltration, ultimately playing a role in responses to cancer therapies. Therefore, understanding “cancer autophagy” could help turn this cellular waste-management service into a powerful ally for specific therapeutics. For instance, numerous regulatory mechanisms of the autophagic machinery can contribute to the anti-tumor properties of oncolytic viruses (OVs), which comprise a diverse class of replication-competent viruses with potential as cancer immunotherapeutics. In that context, autophagy can either: promote OV anti-tumor effects by enhancing infectivity and replication, mediating oncolysis, and inducing autophagic and immunogenic cell death; or reduce OV cytotoxicity by providing survival cues to tumor cells. These properties make the catabolic process of autophagy an attractive target for therapeutic combinations looking to enhance the efficacy of OVs. In this article, we review the complicated role of autophagy in cancer initiation and development, its effect on modulating OVs and immunity, and we discuss recent progress and opportunities/challenges in targeting autophagy to enhance oncolytic viral immunotherapy. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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17 pages, 604 KiB

Open AccessReview

The Dual Role of Autophagy in Crizotinib-Treated ALK⁺ ALCL: From the Lymphoma Cells Drug Resistance to Their Demise

by Estelle Espinos, Raymond Lai and Sylvie Giuriato

Cells 2021, 10(10), 2517; https://doi.org/10.3390/cells10102517 - 23 Sep 2021

Cited by 5 | Viewed by 2634

Abstract

Autophagy has been described as harboring a dual role in cancer development and therapy. Depending on the context, it can exert either pro-survival or pro-death functions. Here, we review what is known about autophagy in crizotinib-treated ALK⁺ ALCL. We first present our [...] Read more.

Autophagy has been described as harboring a dual role in cancer development and therapy. Depending on the context, it can exert either pro-survival or pro-death functions. Here, we review what is known about autophagy in crizotinib-treated ALK⁺ ALCL. We first present our main findings on the role and regulation of autophagy in these cells. Then, we provide literature-driven hypotheses that could explain mechanistically the pro-survival properties of autophagy in crizotinib-treated bulk and stem-like ALK⁺ ALCL cells. Finally, we discuss how the potentiation of autophagy, which occurs with combined therapies (ALK and BCL2 or ALK and RAF1 co-inhibition), could convert it from a survival mechanism to a pro-death process. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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24 pages, 2875 KiB

Open AccessReview

The Multifaceted Functions of Autophagy in Breast Cancer Development and Treatment

by Nicolas J. Niklaus, Igor Tokarchuk, Mara Zbinden, Anna M. Schläfli, Paola Maycotte and Mario P. Tschan

Cells 2021, 10(6), 1447; https://doi.org/10.3390/cells10061447 - 9 Jun 2021

Cited by 43 | Viewed by 5645

Abstract

Macroautophagy (herein referred to as autophagy) is a complex catabolic process characterized by the formation of double-membrane vesicles called autophagosomes. During this process, autophagosomes engulf and deliver their intracellular content to lysosomes, where they are degraded by hydrolytic enzymes. Thereby, autophagy provides energy [...] Read more.

Macroautophagy (herein referred to as autophagy) is a complex catabolic process characterized by the formation of double-membrane vesicles called autophagosomes. During this process, autophagosomes engulf and deliver their intracellular content to lysosomes, where they are degraded by hydrolytic enzymes. Thereby, autophagy provides energy and building blocks to maintain cellular homeostasis and represents a dynamic recycling mechanism. Importantly, the clearance of damaged organelles and aggregated molecules by autophagy in normal cells contributes to cancer prevention. Therefore, the dysfunction of autophagy has a major impact on the cell fate and can contribute to tumorigenesis. Breast cancer is the most common cancer in women and has the highest mortality rate among all cancers in women worldwide. Breast cancer patients often have a good short-term prognosis, but long-term survivors often experience aggressive recurrence. This phenomenon might be explained by the high heterogeneity of breast cancer tumors rendering mammary tumors difficult to target. This review focuses on the mechanisms of autophagy during breast carcinogenesis and sheds light on the role of autophagy in the traits of aggressive breast cancer cells such as migration, invasion, and therapeutic resistance. Full article

(This article belongs to the Special Issue Molecular Connections between Autophagy, Programmed Cell Death Pathways and Differentiation in Cancer Cells)

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