Cancers

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13 pages, 1762 KiB

Open AccessArticle

Partial Truncation of the C-Terminal Domain of PTCH1 in Cancer Enhances Autophagy and Metabolic Adaptability

by Begoña Caballero-Ruiz, Danai S. Gkotsi, Hattie Ollerton, Cintli C. Morales-Alcala, Rosa Bordone, Georgia M. L. Jenkins, Laura Di Magno, Gianluca Canettieri and Natalia A. Riobo-Del Galdo

Cancers 2023, 15(2), 369; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15020369 - 6 Jan 2023

Viewed by 1963

Abstract

The Hedgehog receptor, Patched1 (PTCH1), is a well-known tumour suppressor. While the tumour suppressor’s activity is mostly ascribed to its function as a repressor of the canonical Smoothened/Gli pathway, its C-terminal domain (CTD) was reported to have additional non-canonical functions. One of them [...] Read more.

The Hedgehog receptor, Patched1 (PTCH1), is a well-known tumour suppressor. While the tumour suppressor’s activity is mostly ascribed to its function as a repressor of the canonical Smoothened/Gli pathway, its C-terminal domain (CTD) was reported to have additional non-canonical functions. One of them is the reduction of autophagic flux through direct interaction with the Unc-51, like the autophagy activating kinase (ULK) complex subunit autophagy-related protein-101 (ATG101). With the aim of investigating whether this function of PTCH1 is important in cancer cell fitness, we first identified frameshift mutations in the CTD of PTCH1 in cancer databases. We demonstrated that those mutations disrupt PTCH1 interaction with ATG101 and increase autophagic flux. Using deletion mutants of the PTCH1 CTD in co-immunoprecipitation studies, we established that the 1309–1447 region is necessary and sufficient for interaction with ATG101. We next showed that the three most common PTCH1 CTD mutations in endometrial, stomach and colon adenocarcinomas that cause frameshifts at S1203, R1308 and Y1316 lack the ability to interact with ATG101 and limit autophagic flux, determined by bafilomycin A1-sensitive accumulation of the autophagy markers LC3BII and p62. We next engineered PTCH1 indel mutations at S1223 by CRISPR/Cas9 in SW620 colon cancer cells. Comparison of two independent clones harbouring PTCH1 S1223fs mutations to their isogenic parental cell lines expressing wild-type PTCH1 showed a significant increase in basal and rapamycin-stimulated autophagic flux, as predicted by loss of ATG101 interaction. Furthermore, the PTCH1 CTD mutant cells displayed increased proliferation in the presence of rapamycin and reduced sensitivity to glycolysis inhibitors. Our findings suggest that loss of the PTCH1-ATG101 interaction by mutations in the CTD of PTCH1 in cancer might confer a selective advantage by stimulating autophagy and facilitating adaptation to nutrient deprivation conditions. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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21 pages, 4130 KiB

Open AccessArticle

A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer

by Adrià Molero-Valenzuela, Pere Fontova, Daniel Alonso-Carrillo, Israel Carreira-Barral, Ana Aurora Torres, María García-Valverde, Cristina Benítez-García, Ricardo Pérez-Tomás, Roberto Quesada and Vanessa Soto-Cerrato

Cancers 2022, 14(14), 3387; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14143387 - 12 Jul 2022

Cited by 3 | Viewed by 2196

Abstract

Overcoming resistance is one of the most challenging features in current anticancer therapy. Autophagy is a cellular process that confers resistance in some advanced tumors, since it enables cancer cells to adapt to stressful situations, such as anticancer treatments. Hence, the inhibition of [...] Read more.

Overcoming resistance is one of the most challenging features in current anticancer therapy. Autophagy is a cellular process that confers resistance in some advanced tumors, since it enables cancer cells to adapt to stressful situations, such as anticancer treatments. Hence, the inhibition of this cytoprotective autophagy leads to tumor cells sensitization and death. In this regard, we designed a novel potent anionophore compound that specifically targets lysosomes, called LAI-1 (late-stage autophagy inhibitor-1), and evaluated its role in blocking autophagy and its potential anticancer effects in three lung cancer cell lines from different histological subtypes. Compared to other autophagy inhibitors, such as chloroquine and 3-Methyladenine, the LAI-1 treatment induced more potent anticancer effects in all tested cancer cells. LAI-1 was able to efficiently target and deacidify lysosomes, while acidifying cytoplasmic pH. Consequently, LAI-1 efficiently blocked autophagy, indicated by the increased LC3-II/I ratio and p62/SQSTM1 levels. Moreover, no colocalization was observed between autophagosomes, marked with LC3 or p62/SQSTM1, and lysosomes, stained with LAMP-1, after the LAI-1 treatment, indicating the blockage of autophagolysosome formation. Furthermore, LAI-1 induced cell death by activating apoptosis (enhancing the cleavage of caspase-3 and PARP) or necrosis, depending on the cancer cell line. Finally, LAI-1 sensitized cancer cells to the first-line chemotherapeutic agent cisplatin. Altogether, LAI-1 is a new late-stage autophagy inhibitor that causes lysosomal dysfunction and the blockage of autophagolysosome formation, as well as potently induces cancer cell death and sensitization to conventional treatments at lower concentrations than other known autophagy inhibitors, appearing as a potential new therapeutic approach to overcome cancer resistance. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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18 pages, 3256 KiB

Open AccessArticle

diTFPP, a Phenoxyphenol, Sensitizes Hepatocellular Carcinoma Cells to C₂-Ceramide-Induced Autophagic Stress by Increasing Oxidative Stress and ER Stress Accompanied by LAMP2 Hypoglycosylation

by Chien-Chih Chiu, Yen-Chun Chen, Yung-Ding Bow, Jeff Yi-Fu Chen, Wangta Liu, Jau-Ling Huang, En-De Shu, Yen-Ni Teng, Chang-Yi Wu and Wen-Tsan Chang

Cancers 2022, 14(10), 2528; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102528 - 20 May 2022

Cited by 8 | Viewed by 2320

Abstract

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the leading cause of cancer-related mortality worldwide. Chemotherapy is the major treatment modality for advanced or unresectable HCC; unfortunately, chemoresistance results in a poor prognosis for HCC patients. Exogenous ceramide, a sphingolipid, [...] Read more.

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the leading cause of cancer-related mortality worldwide. Chemotherapy is the major treatment modality for advanced or unresectable HCC; unfortunately, chemoresistance results in a poor prognosis for HCC patients. Exogenous ceramide, a sphingolipid, has been well documented to exert anticancer effects. However, recent reports suggest that sphingolipid metabolism in ceramide-resistant cancer cells favors the conversion of exogenous ceramides to prosurvival sphingolipids, conferring ceramide resistance to cancer cells. However, the mechanism underlying ceramide resistance remains unclear. We previously demonstrated that diTFPP, a novel phenoxyphenol compound, enhances the anti-HCC effect of C₂-ceramide. Here, we further clarified that treatment with C₂-ceramide alone increases the protein level of CERS2, which modulates sphingolipid metabolism to favor the conversion of C₂-ceramide to prosurvival sphingolipids in HCC cells, thus activating the unfolded protein response (UPR), which further initiates autophagy and the reversible senescence-like phenotype (SLP), ultimately contributing to C₂-ceramide resistance in these cells. However, cotreatment with diTFPP and ceramide downregulated the protein level of CERS2 and increased oxidative and endoplasmic reticulum (ER) stress. Furthermore, insufficient LAMP2 glycosylation induced by diTFPP/ceramide cotreatment may cause the failure of autophagosome–lysosome fusion, eventually lowering the threshold for triggering cell death in response to C₂-ceramide. Our study may shed light on the mechanism of ceramide resistance and help in the development of adjuvants for ceramide-based cancer therapeutics. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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14 pages, 2028 KiB

Open AccessFeature PaperArticle

Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells

by Marine Dupont, Mathilde Huart, Claire Lauvinerie, Audrey Bidet, Amélie Valérie Guitart, Arnaud Villacreces, Isabelle Vigon, Vanessa Desplat, Ali El Habhab, Arnaud Pigneux, Zoran Ivanovic, Philippe Brunet De la Grange, Pierre-Yves Dumas and Jean-Max Pasquet

Cancers 2022, 14(2), 453; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020453 - 17 Jan 2022

Cited by 5 | Viewed by 3048

Abstract

Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, [...] Read more.

Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, we demonstrate in vitro that FLT3-ITD AML cells decrease their repopulating capacity when Vps34 is inhibited. Ex vivo, AML FLT3-ITD blasts treated with Vps34 inhibitors recovered proliferation more slowly due to an increase an apoptosis. In vivo, mice engrafted with FLT3-ITD AML MV4-11 cells have the invasion of the bone marrow and blood in 2 weeks. After 4 weeks of FLT3 TKI treatment with gilteritinib, the leukemic burden had strongly decreased and deep remission was observed. When treatment was discontinued, mice relapsed rapidly. In contrast, Vps34 inhibition strongly decreased the relapse rate, and even more so in association with mobilization by G-CSF and AMD3100. These results demonstrate that remission offers the therapeutic window for a regimen using Vps34 inhibition combined with mobilization to target persistent leukemic stem cells and thus decrease the relapse rate. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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19 pages, 2481 KiB

Open AccessArticle

Metabolic Rewiring Is Essential for AML Cell Survival to Overcome Autophagy Inhibition by Loss of ATG3

by Fatima Baker, Ibrahim H. Polat, Khalil Abou-El-Ardat, Islam Alshamleh, Marlyn Thoelken, Daniel Hymon, Andrea Gubas, Sebastian E. Koschade, Jonas B. Vischedyk, Manuel Kaulich, Harald Schwalbe, Shabnam Shaid and Christian H. Brandts

Cancers 2021, 13(23), 6142; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13236142 - 6 Dec 2021

Cited by 5 | Viewed by 2890

Abstract

Autophagy is an important survival mechanism that allows recycling of nutrients and removal of damaged organelles and has been shown to contribute to the proliferation of acute myeloid leukemia (AML) cells. However, little is known about the mechanism by which autophagy- dependent AML [...] Read more.

Autophagy is an important survival mechanism that allows recycling of nutrients and removal of damaged organelles and has been shown to contribute to the proliferation of acute myeloid leukemia (AML) cells. However, little is known about the mechanism by which autophagy- dependent AML cells can overcome dysfunctional autophagy. In our study we identified autophagy related protein 3 (ATG3) as a crucial autophagy gene for AML cell proliferation by conducting a CRISPR/Cas9 dropout screen with a library targeting around 200 autophagy-related genes. shRNA-mediated loss of ATG3 impaired autophagy function in AML cells and increased their mitochondrial activity and energy metabolism, as shown by elevated mitochondrial ROS generation and mitochondrial respiration. Using tracer-based NMR metabolomics analysis we further demonstrate that the loss of ATG3 resulted in an upregulation of glycolysis, lactate production, and oxidative phosphorylation. Additionally, loss of ATG3 strongly sensitized AML cells to the inhibition of mitochondrial metabolism. These findings highlight the metabolic vulnerabilities that AML cells acquire from autophagy inhibition and support further exploration of combination therapies targeting autophagy and mitochondrial metabolism in AML. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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20 pages, 8037 KiB

Open AccessArticle

Quinacrine-Induced Autophagy in Ovarian Cancer Triggers Cathepsin-L Mediated Lysosomal/Mitochondrial Membrane Permeabilization and Cell Death

by Prabhu Thirusangu, Christopher L. Pathoulas, Upasana Ray, Yinan Xiao, Julie Staub, Ling Jin, Ashwani Khurana and Viji Shridhar

Cancers 2021, 13(9), 2004; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092004 - 21 Apr 2021

Cited by 20 | Viewed by 3432

Abstract

We previously reported that the antimalarial compound quinacrine (QC) induces autophagy in ovarian cancer cells. In the current study, we uncovered that QC significantly upregulates cathepsin L (CTSL) but not cathepsin B and D levels, implicating the specific role of CTSL in promoting [...] Read more.

We previously reported that the antimalarial compound quinacrine (QC) induces autophagy in ovarian cancer cells. In the current study, we uncovered that QC significantly upregulates cathepsin L (CTSL) but not cathepsin B and D levels, implicating the specific role of CTSL in promoting QC-induced autophagic flux and apoptotic cell death in OC cells. Using a Magic Red^® cathepsin L activity assay and LysoTracker red, we discerned that QC-induced CTSL activation promotes lysosomal membrane permeability (LMP) resulting in the release of active CTSL into the cytosol to promote apoptotic cell death. We found that QC-induced LMP and CTSL activation promotes Bid cleavage, mitochondrial outer membrane permeabilization (MOMP), and mitochondrial cytochrome-c release. Genetic (shRNA) and pharmacological (Z-FY(tBU)-DMK) inhibition of CTSL markedly reduces QC-induced autophagy, LMP, MOMP, apoptosis, and cell death; whereas induced overexpression of CTSL in ovarian cancer cell lines has an opposite effect. Using recombinant CTSL, we identified p62/SQSTM1 as a novel substrate of CTSL, suggesting that CTSL promotes QC-induced autophagic flux. CTSL activation is specific to QC-induced autophagy since no CTSL activation is seen in ATG5 knockout cells or with the anti-malarial autophagy-inhibiting drug chloroquine. Importantly, we showed that upregulation of CTSL in QC-treated HeyA8MDR xenografts corresponds with attenuation of p62, upregulation of LC3BII, cytochrome-c, tBid, cleaved PARP, and caspase3. Taken together, the data suggest that QC-induced autophagy and CTSL upregulation promote a positive feedback loop leading to excessive autophagic flux, LMP, and MOMP to promote QC-induced cell death in ovarian cancer cells. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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Graphical abstract

19 pages, 5993 KiB

Open AccessArticle

New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function

by Yuanyuan Fu, Qianqian Gu, Li Luo, Jiecheng Xu, Yuping Luo, Fan Xia, Fanghai Han, Liang Hong, Xiao-Ming Yin, Zhiying Huang and Min Li

Cancers 2020, 12(6), 1523; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061523 - 10 Jun 2020

Cited by 17 | Viewed by 2984

Abstract

Autophagy inhibition has been proposed to be a potential therapeutic strategy for cancer, however, few autophagy inhibitors have been developed. Recent studies have indicated that lysosome and autophagy related 4B cysteine peptidase (ATG4B) are two promising targets in autophagy for cancer therapy. Although [...] Read more.

Autophagy inhibition has been proposed to be a potential therapeutic strategy for cancer, however, few autophagy inhibitors have been developed. Recent studies have indicated that lysosome and autophagy related 4B cysteine peptidase (ATG4B) are two promising targets in autophagy for cancer therapy. Although some inhibitors of either lysosome or ATG4B were reported, there are limitations in the use of these single target compounds. Considering multi-functional drugs have advantages, such as high efficacy and low toxicity, we first screened and validated a batch of compounds designed and synthesized in our laboratory by combining the screening method of ATG4B inhibitors and the identification method of lysosome inhibitors. ATG4B activity was effectively inhibited in vitro. Moreover, 163N inhibited autophagic flux and caused the accumulation of autolysosomes. Further studies demonstrated that 163N could not affect the autophagosome-lysosome fusion but could cause lysosome dysfunction. In addition, 163N diminished tumor cell viability and impaired the development of colorectal cancer in vivo. The current study findings indicate that the dual effect inhibitor 163N offers an attractive new anti-cancer drug and compounds having a combination of lysosome inhibition and ATG4B inhibition are a promising therapeutic strategy for colorectal cancer therapy. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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Review

Jump to: Research

20 pages, 6492 KiB

Open AccessReview

Autophagy, Oxidative Stress and Cancer Development

by Elisabeth Taucher, Iurii Mykoliuk, Melanie Fediuk and Freyja-Maria Smolle-Juettner

Cancers 2022, 14(7), 1637; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071637 - 23 Mar 2022

Cited by 24 | Viewed by 3212

Abstract

Autophagy is an important cellular repair mechanism, aiming at sequestering misfolded and dysfunctional proteins and damaged cell organelles. Dysfunctions in the autophagy process have been linked to several diseases, like infectious and neurodegenerative diseases, type II diabetes mellitus and cancer. Living organisms are [...] Read more.

Autophagy is an important cellular repair mechanism, aiming at sequestering misfolded and dysfunctional proteins and damaged cell organelles. Dysfunctions in the autophagy process have been linked to several diseases, like infectious and neurodegenerative diseases, type II diabetes mellitus and cancer. Living organisms are constantly subjected to some degree of oxidative stress, mainly induced by reactive oxygen and nitrogen species. It has been shown that autophagy is readily induced by reactive oxygen species (ROS) upon nutrient deprivation. In recent years, research has increasingly focused on outlining novel therapeutic targets related to the autophagy process. With this review of the literature, we want to give an overview about the link between autophagy, oxidative stress and carcinogenesis. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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46 pages, 7112 KiB

Open AccessReview

Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components

by Entaz Bahar, Sun-Young Han, Ji-Ye Kim and Hyonok Yoon

Cancers 2022, 14(6), 1462; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061462 - 12 Mar 2022

Cited by 32 | Viewed by 5279

Abstract

Cancer chemotherapy resistance is one of the most critical obstacles in cancer therapy. One of the well-known mechanisms of chemotherapy resistance is the change in the mitochondrial death pathways which occur when cells are under stressful situations, such as chemotherapy. Mitophagy, or mitochondrial [...] Read more.

Cancer chemotherapy resistance is one of the most critical obstacles in cancer therapy. One of the well-known mechanisms of chemotherapy resistance is the change in the mitochondrial death pathways which occur when cells are under stressful situations, such as chemotherapy. Mitophagy, or mitochondrial selective autophagy, is critical for cell quality control because it can efficiently break down, remove, and recycle defective or damaged mitochondria. As cancer cells use mitophagy to rapidly sweep away damaged mitochondria in order to mediate their own drug resistance, it influences the efficacy of tumor chemotherapy as well as the degree of drug resistance. Yet despite the importance of mitochondria and mitophagy in chemotherapy resistance, little is known about the precise mechanisms involved. As a consequence, identifying potential therapeutic targets by analyzing the signal pathways that govern mitophagy has become a vital research goal. In this paper, we review recent advances in mitochondrial research, mitophagy control mechanisms, and their implications for our understanding of chemotherapy resistance. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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19 pages, 1827 KiB

Open AccessReview

The Role of Decorin Proteoglycan in Mitophagy

by Thomas Neill and Renato V. Iozzo

Cancers 2022, 14(3), 804; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030804 - 4 Feb 2022

Cited by 9 | Viewed by 4703

Abstract

Proteoglycans are emerging as critical regulators of intracellular catabolism. This rise in prominence has transformed our basic understanding and alerted us to the existence of non-canonical pathways, independent of nutrient deprivation, that potently control the autophagy downstream of a cell surface receptor. As [...] Read more.

Proteoglycans are emerging as critical regulators of intracellular catabolism. This rise in prominence has transformed our basic understanding and alerted us to the existence of non-canonical pathways, independent of nutrient deprivation, that potently control the autophagy downstream of a cell surface receptor. As a member of the small leucine-rich proteoglycan gene family, decorin has single-handedly pioneered the connection between extracellular matrix signaling and autophagy regulation. Soluble decorin evokes protracted endothelial cell autophagy via Peg3 and breast carcinoma cell mitophagy via mitostatin by interacting with VEGFR2 or the MET receptor tyrosine kinase, respectively. In this paper, we give a mechanistic perspective of the vital factors underlying the nutrient-independent, SLRP-dependent programs utilized for autophagic and/or mitophagic progression in breast cancer. Future protein therapies based on decorin (or fellow proteoglycan members) will represent a quantum leap forward in transforming autophagic progression into a powerful tool to control intracellular cell catabolism from the outside. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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19 pages, 1710 KiB

Open AccessReview

The Intricate Interplay between Cell Cycle Regulators and Autophagy in Cancer

by Dorian V. Ziegler, Katharina Huber and Lluis Fajas

Cancers 2022, 14(1), 153; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010153 - 29 Dec 2021

Cited by 10 | Viewed by 2867

Abstract

In the past decade, cell cycle regulators have extended their canonical role in cell cycle progression to the regulation of various cellular processes, including cellular metabolism. The regulation of metabolism is intimately connected with the function of autophagy, a catabolic process that promotes [...] Read more.

In the past decade, cell cycle regulators have extended their canonical role in cell cycle progression to the regulation of various cellular processes, including cellular metabolism. The regulation of metabolism is intimately connected with the function of autophagy, a catabolic process that promotes the efficient recycling of endogenous components from both extrinsic stress, e.g., nutrient deprivation, and intrinsic sub-lethal damage. Mediating cellular homeostasis and cytoprotection, autophagy is found to be dysregulated in numerous pathophysiological contexts, such as cancer. As an adaptative advantage, the upregulation of autophagy allows tumor cells to integrate stress signals, escaping multiple cell death mechanisms. Nevertheless, the precise role of autophagy during tumor development and progression remains highly context-dependent. Recently, multiple articles has suggested the importance of various cell cycle regulators in the modulation of autophagic processes. Here, we review the current clues indicating that cell-cycle regulators, including cyclin-dependent kinase inhibitors (CKIs), cyclin-dependent kinases (CDKs), and E2F transcription factors, are intrinsically linked to the regulation of autophagy. As an increasing number of studies highlight the importance of autophagy in cancer progression, we finally evoke new perspectives in therapeutic avenues that may include both cell cycle inhibitors and autophagy modulators to synergize antitumor efficacy. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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37 pages, 1930 KiB

Open AccessReview

Understanding the Role of Autophagy in Cancer Formation and Progression Is a Real Opportunity to Treat and Cure Human Cancers

by Simone Patergnani, Sonia Missiroli, Giampaolo Morciano, Mariasole Perrone, Cristina M. Mantovani, Gabriele Anania, Francesco Fiorica, Paolo Pinton and Carlotta Giorgi

Cancers 2021, 13(22), 5622; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225622 - 10 Nov 2021

Cited by 22 | Viewed by 7366

Abstract

The malignant transformation of a cell produces the accumulation of several cellular adaptions. These changes determine variations in biological processes that are necessary for a cancerous cell to survive during stressful conditions. Autophagy is the main nutrient recycling and metabolic adaptor mechanism in [...] Read more.

The malignant transformation of a cell produces the accumulation of several cellular adaptions. These changes determine variations in biological processes that are necessary for a cancerous cell to survive during stressful conditions. Autophagy is the main nutrient recycling and metabolic adaptor mechanism in eukaryotic cells, represents a continuous source of energy and biomolecules, and is fundamental to preserve the correct cellular homeostasis during unfavorable conditions. In recent decades, several findings demonstrate a close relationship between autophagy, malignant transformation, and cancer progression. The evidence suggests that autophagy in the cancer context has a bipolar role (it may act as a tumor suppressor and as a mechanism of cell survival for established tumors) and demonstrates that the targeting of autophagy may represent novel therapeutic opportunities. Accordingly, the modulation of autophagy has important clinical benefits in patients affected by diverse cancer types. Currently, about 30 clinical trials are actively investigating the efficacy of autophagy modulators to enhance the efficacy of cytotoxic chemotherapy treatments. A deeper understanding of the molecular pathways regulating autophagy in the cancer context will provide new ways to target autophagy for improving the therapeutic benefits. Herein, we describe how autophagy participates during malignant transformation and cancer progression, and we report the ultimate efforts to translate this knowledge into specific therapeutic approaches to treat and cure human cancers. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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24 pages, 1197 KiB

Open AccessReview

Autophagy in Cisplatin Nephrotoxicity during Cancer Therapy

by Xiaoru Hu, Zhengwei Ma, Lu Wen, Siyao Li and Zheng Dong

Cancers 2021, 13(22), 5618; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225618 - 10 Nov 2021

Cited by 18 | Viewed by 3431

Abstract

Cisplatin is a widely used chemotherapeutic agent but its clinical use is often limited by nephrotoxicity. Autophagy is a lysosomal degradation pathway that removes protein aggregates and damaged or dysfunctional cellular organelles for maintaining cell homeostasis. Upon cisplatin exposure, autophagy is rapidly activated [...] Read more.

Cisplatin is a widely used chemotherapeutic agent but its clinical use is often limited by nephrotoxicity. Autophagy is a lysosomal degradation pathway that removes protein aggregates and damaged or dysfunctional cellular organelles for maintaining cell homeostasis. Upon cisplatin exposure, autophagy is rapidly activated in renal tubule cells to protect against acute cisplatin nephrotoxicity. Mechanistically, the protective effect is mainly related to the clearance of damaged mitochondria via mitophagy. The role and regulation of autophagy in chronic kidney problems after cisplatin treatment are currently unclear, despite the significance of research in this area. In cancers, autophagy may prevent tumorigenesis, but autophagy may reduce the efficacy of chemotherapy by protecting cancer cells. Future research should focus on developing drugs that enhance the anti-tumor effects of cisplatin while protecting kidneys during cisplatin chemotherapy. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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21 pages, 711 KiB

Open AccessReview

Autophagy in Cancer Therapy—Molecular Mechanisms and Current Clinical Advances

by Ingo Ganzleben, Markus F. Neurath and Christoph Becker

Cancers 2021, 13(21), 5575; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215575 - 8 Nov 2021

Cited by 12 | Viewed by 3568

Abstract

Autophagy is a crucial general survival tactic of mammalian cells. It describes the capability of cells to disassemble and partially recycle cellular components (e.g., mitochondria) in case they are damaged and pose a risk to cell survival or simply if their resources are [...] Read more.

Autophagy is a crucial general survival tactic of mammalian cells. It describes the capability of cells to disassemble and partially recycle cellular components (e.g., mitochondria) in case they are damaged and pose a risk to cell survival or simply if their resources are urgently needed elsewhere at the time. Autophagy-associated pathomechanisms have been increasingly recognized as important disease mechanisms in non-malignant (neurodegeneration, diffuse parenchymal lung disease) and malignant conditions alike. However, the overall consequences of autophagy for the organism depend particularly on the greater context in which autophagy occurs, such as the cell type or whether the cell is proliferating. In cancer, autophagy sustains cancer cell survival under challenging, i.e., resource-depleted, conditions. However, this leads to situations in which cancer cells are completely dependent on autophagy. Accordingly, autophagy represents a promising yet complex target in cancer treatment with therapeutically induced increase and decrease of autophagic flux as important therapeutic principles. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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14 pages, 1112 KiB

Open AccessReview

Oncolytic Virus-Induced Autophagy in Glioblastoma

by Margarita Kamynina, Salome Tskhovrebova, Jawad Fares, Peter Timashev, Anastasia Laevskaya and Ilya Ulasov

Cancers 2021, 13(14), 3482; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143482 - 12 Jul 2021

Cited by 7 | Viewed by 3429

Abstract

Autophagy is a catabolic process that allows cells to scavenge damaged organelles and produces energy to maintain cellular homeostasis. It is also an effective defense method for cells, which allows them to identify an internalized pathogen and destroy it through the fusion of [...] Read more.

Autophagy is a catabolic process that allows cells to scavenge damaged organelles and produces energy to maintain cellular homeostasis. It is also an effective defense method for cells, which allows them to identify an internalized pathogen and destroy it through the fusion of the autophagosome and lysosomes. Recent reports have demonstrated that various chemotherapeutic agents and viral gene therapeutic vehicles provide therapeutic advantages for patients with glioblastoma as monotherapy or in combination with standards of care. Despite nonstop efforts to develop effective antiglioma therapeutics, tumor-induced autophagy in some studies manifests tumor resistance and glioma progression. Here, we explore the functional link between autophagy regulation mediated by oncolytic viruses and discuss how intracellular interactions control autophagic signaling in glioblastoma. Autophagy induced by oncolytic viruses plays a dual role in cell death and survival. On the one hand, autophagy stimulation has mostly led to an increase in cytotoxicity mediated by the oncolytic virus, but, on the other hand, autophagy is also activated as a cell defense mechanism against intracellular pathogens and modulates antiviral activity through the induction of ER stress and unfolded protein response (UPR) signaling. Despite the fact that the moment of switch between autophagic prosurvival and prodeath modes remains to be known, in the context of oncolytic virotherapy, cytotoxic autophagy is a crucial mechanism of cancer cell death. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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18 pages, 1728 KiB

Open AccessReview

Lysosomal Calcium Channels in Autophagy and Cancer

by Yi Wu, Peng Huang and Xian-Ping Dong

Cancers 2021, 13(6), 1299; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13061299 - 15 Mar 2021

Cited by 27 | Viewed by 4533

Abstract

Ca²⁺ is pivotal intracellular messenger that coordinates multiple cell functions such as fertilization, growth, differentiation, and viability. Intracellular Ca²⁺ signaling is regulated by both extracellular Ca²⁺ entry and Ca²⁺ release from intracellular stores. Apart from working as the cellular [...] Read more.

Ca²⁺ is pivotal intracellular messenger that coordinates multiple cell functions such as fertilization, growth, differentiation, and viability. Intracellular Ca²⁺ signaling is regulated by both extracellular Ca²⁺ entry and Ca²⁺ release from intracellular stores. Apart from working as the cellular recycling center, the lysosome has been increasingly recognized as a significant intracellular Ca²⁺ store that provides Ca²⁺ to regulate many cellular processes. The lysosome also talks to other organelles by releasing and taking up Ca²⁺. In lysosomal Ca²⁺-dependent processes, autophagy is particularly important, because it has been implicated in many human diseases including cancer. This review will discuss the major components of lysosomal Ca²⁺ stores and their roles in autophagy and human cancer progression. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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36 pages, 2808 KiB

Open AccessReview

Challenges and Therapeutic Opportunities of Autophagy in Cancer Therapy

by Valdenizia R. Silva, Sara P. Neves, Luciano de S. Santos, Rosane B. Dias and Daniel P. Bezerra

Cancers 2020, 12(11), 3461; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113461 - 20 Nov 2020

Cited by 34 | Viewed by 5692

Abstract

Autophagy is a physiological cellular process that is crucial for development and can occurs in response to nutrient deprivation or metabolic disorders. Interestingly, autophagy plays a dual role in cancer cells—while in some situations, it has a cytoprotective effect that causes chemotherapy resistance, [...] Read more.

Autophagy is a physiological cellular process that is crucial for development and can occurs in response to nutrient deprivation or metabolic disorders. Interestingly, autophagy plays a dual role in cancer cells—while in some situations, it has a cytoprotective effect that causes chemotherapy resistance, in others, it has a cytotoxic effect in which some compounds induce autophagy-mediated cell death. In this review, we summarize strategies aimed at autophagy for the treatment of cancer, including studies of drugs that can modulate autophagy-mediated resistance, and/or drugs that cause autophagy-mediated cancer cell death. In addition, the role of autophagy in the biology of cancer stem cells has also been discussed. Full article

(This article belongs to the Special Issue Targeting Autophagy for Cancer Treatment)

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