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Elshazly AM, Elzahed AA, Gewirtz DA. Evidence for cytoprotective autophagy in response to HER2-targeted monoclonal antibodies. J Pharmacol Exp Ther 2025; 392:100007. [PMID: 39892993 DOI: 10.1124/jpet.123.002048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 02/03/2024] [Accepted: 02/11/2024] [Indexed: 03/09/2024] Open
Abstract
The advent of HER2-targeted monoclonal antibodies such as trastuzumab has significantly improved the clinical outcomes for patients with breast cancer overexpressing HER2 and, more recently, also for gastric cancers. However, the development of resistance, as is frequently the case for other antineoplastic modalities, constrains their clinical efficacy. Multiple molecular mechanisms and signaling pathways have been investigated for their potential involvement in the development of resistance to HER2-targeted therapies, among which is autophagy. Autophagy is an inherent cellular mechanism whereby cytoplasmic components are selectively degraded to maintain cellular homeostasis via the generation of energy and metabolic intermediates. Although the cytoprotective form of autophagy is thought to predominate, other forms of autophagy have also been identified in response to chemotherapeutic agents in various tumor models; these include cytotoxic, cytostatic, and nonprotective functional forms of autophagy. In this review, we provide an overview of the autophagic machinery induced in response to HER2-targeted monoclonal antibodies, with a focus on trastuzumab and trastuzumab-emtansine, in an effort to determine whether autophagy targeting or modulation could be translated clinically to increase their effectiveness and/or overcome the development of resistance. SIGNIFICANCE STATEMENT: This manuscript is one in a series of papers that interrogate the role(s) of the autophagy induced in response to antineoplastic agents in various cancer models. This series of papers was developed in an effort to establish whether autophagy targeting or modulation is likely to be an effective adjuvant strategy to increase the efficacy of cancer chemotherapeutic agents. This review explores the relationship between the autophagic machinery and HER2-targeted therapies.
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Affiliation(s)
- Ahmed M Elshazly
- Department of Pharmacology and Toxicology, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - Aya A Elzahed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - David A Gewirtz
- Department of Pharmacology and Toxicology, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
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Kandasamy T, Sarkar S, Ghosh SS. Harnessing Drug Repurposing to Combat Breast Cancer by Targeting Altered Metabolism and Epithelial-to-Mesenchymal Transition Pathways. ACS Pharmacol Transl Sci 2024; 7:3780-3794. [PMID: 39698277 PMCID: PMC11650739 DOI: 10.1021/acsptsci.4c00545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 10/15/2024] [Accepted: 10/21/2024] [Indexed: 12/20/2024]
Abstract
Breast cancer remains one of the most prevalent and challenging cancers to treat due to its complexity and heterogenicity. Cellular processes such as metabolic reprogramming and epithelial-to-mesenchymal transition (EMT) contribute to the complexity of breast cancer by driving uncontrolled cell division, metastasis, and resistance to therapies. Strategically targeting these intricate pathways can effectively impede breast cancer progression, thereby revealing significant potential for therapeutic interventions. Among various emerging therapeutic approaches, drug repurposing offers a promising avenue for enhancing clinical outcomes. In recent years, high-throughput screening, QSAR, and network pharmacology have been widely employed to identify promising repurposed drugs. As an outcome, several drugs, such as Metformin, Itraconazole, Pimozide, and Disulfiram, were repurposed to regulate metabolic and EMT pathways. Moreover, strategies such as combination therapy, targeted delivery, and personalized medicine were utilized to enhance the efficacy and specificity of the repurposed drugs. This review focuses on the potential of targeting altered metabolism and EMT in breast cancer through drug repurposing. It also highlights recent advancements in drug screening techniques, associated limitations, and strategies to overcome these challenges.
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Affiliation(s)
- Thirukumaran Kandasamy
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Guwahati-39, Assam India
| | - Shilpi Sarkar
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Guwahati-39, Assam India
| | - Siddhartha Sankar Ghosh
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Guwahati-39, Assam India
- Centre
for Nanotechnology, Indian Institute of
Technology Guwahati, Guwahati-39, Assam India
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3
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Pimentel JM, Zhou JY, Wu GS. Autophagy and cancer therapy. Cancer Lett 2024; 605:217285. [PMID: 39395780 DOI: 10.1016/j.canlet.2024.217285] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/25/2024] [Accepted: 10/03/2024] [Indexed: 10/14/2024]
Abstract
Autophagy is an intracellular degradation process that sequesters cytoplasmic components in double-membrane vesicles known as autophagosomes, which are degraded upon fusion with lysosomes. This pathway maintains the integrity of proteins and organelles while providing energy and nutrients to cells, particularly under nutrient deprivation. Deregulation of autophagy can cause genomic instability, low protein quality, and DNA damage, all of which can contribute to cancer. Autophagy can also be overactivated in cancer cells to aid in cancer cell survival and drug resistance. Emerging evidence indicates that autophagy has functions beyond cargo degradation, including roles in tumor immunity and cancer stem cell survival. Additionally, autophagy can also influence the tumor microenvironment. This feature warrants further investigation of the role of autophagy in cancer, in which autophagy manipulation can improve cancer therapies, including cancer immunotherapy. This review discusses recent findings on the regulation of autophagy and its role in cancer therapy and drug resistance.
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Affiliation(s)
- Julio M Pimentel
- Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA; Institutional Research Academic Career Development Award Program, University of California San Diego, La Jolla, CA, 92093, USA
| | - Jun Ying Zhou
- Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, MI, 48201, USA; Department of Oncology, Wayne State University, Detroit, MI, 48201, USA
| | - Gen Sheng Wu
- Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, MI, 48201, USA; Department of Oncology, Wayne State University, Detroit, MI, 48201, USA; Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
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4
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Cao Z, Tian K, Ran Y, Zhou H, Zhou L, Ding Y, Tang X. Beclin-1: a therapeutic target at the intersection of autophagy, immunotherapy, and cancer treatment. Front Immunol 2024; 15:1506426. [PMID: 39650649 PMCID: PMC11621085 DOI: 10.3389/fimmu.2024.1506426] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 11/01/2024] [Indexed: 12/11/2024] Open
Abstract
The significant identification of Beclin-1's function in regulating autophagy flow signified a significant progression in our understanding of cellular operations. Beclin-1 acts as a scaffold for forming the PI3KC3 complex, controlling autophagy and cellular trafficking processes in a complicated way. This intricate protein has garnered considerable attention due to its substantial impact on the development of tumors. Strong evidence indicates Beclin-1 plays a critical role in controlling autophagy in various human cancer types and its intricate connection with apoptosis and ferroptosis. The potential of Beclin-1 as a viable target for cancer therapy is highlighted by its associations with key autophagy regulators such as AMPK, mTOR, and ATGs. Beclin-1 controls the growth and dissemination of tumors by autophagy. It also affects how tumors react to therapies such as chemotherapy and radiation therapy. The role of Beclin-1 in autophagy can influence apoptosis, depending on whether it supports cell survival or leads to cell death. Beclin-1 plays a crucial role in ferroptosis by increasing ATG5 levels, which in turn promotes autophagy-triggered ferroptosis. Finally, we analyzed the possible function of Beclin-1 in tumor immunology and drug sensitivity in cancers. In general, Beclin-1 has a significant impact on regulating autophagy, offering various potentials for medical intervention and altering our understanding of cancer biology.
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Affiliation(s)
- Zhumin Cao
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Ke Tian
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Yincheng Ran
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Haonan Zhou
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Lei Zhou
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Yana Ding
- Department of Hepatobiliary Surgery, District Traditional Chinese Medicine Hospital, Chongqing, China
| | - Xiaowei Tang
- Department of Hepatobiliary Surgery, District Traditional Chinese Medicine Hospital, Chongqing, China
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5
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Roy A, DePamphilis ML. Selective Termination of Autophagy-Dependent Cancers. Cells 2024; 13:1096. [PMID: 38994949 PMCID: PMC11240546 DOI: 10.3390/cells13131096] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 06/11/2024] [Accepted: 06/12/2024] [Indexed: 07/13/2024] Open
Abstract
The goal of cancer research is to identify characteristics of cancer cells that allow them to be selectively eliminated without harming the host. One such characteristic is autophagy dependence. Cancer cells survive, proliferate, and metastasize under conditions where normal cells do not. Thus, the requirement in cancer cells for more energy and macromolecular biosynthesis can evolve into a dependence on autophagy for recycling cellular components. Recent studies have revealed that autophagy, as well as different forms of cellular trafficking, is regulated by five phosphoinositides associated with eukaryotic cellular membranes and that the enzymes that synthesize them are prime targets for cancer therapy. For example, PIKFYVE inhibitors rapidly disrupt lysosome homeostasis and suppress proliferation in all cells. However, these inhibitors selectively terminate PIKFYVE-dependent cancer cells and cancer stem cells with not having adverse effect on normal cells. Here, we describe the biochemical distinctions between PIKFYVE-sensitive and -insensitive cells, categorize PIKFYVE inhibitors into four groups that differ in chemical structure, target specificity and efficacy on cancer cells and normal cells, identify the mechanisms by which they selectively terminate autophagy-dependent cancer cells, note their paradoxical effects in cancer immunotherapy, and describe their therapeutic applications against cancers.
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Affiliation(s)
- Ajit Roy
- National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Room 6N105, 10 Center Dr., Bethesda, MD 20892-0001, USA;
| | - Melvin L. DePamphilis
- National Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Room 4B413, 6 Center Dr., Bethesda, MD 20892-2790, USA
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6
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Yu T, Rui L, Jiumei Z, Ziwei L, Ying H. Advances in the study of autophagy in breast cancer. Breast Cancer 2024; 31:195-204. [PMID: 38315272 PMCID: PMC10901946 DOI: 10.1007/s12282-023-01541-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 12/25/2023] [Indexed: 02/07/2024]
Abstract
Breast cancer is the most prevalent malignant tumor among women, with a high incidence and mortality rate all year round, which seriously affects women's health. Autophagy, a well-conserved cellular process inherent in eukaryotic organisms, plays a pivotal role in degrading damaged proteins and organelles, recycling their breakdown products to aid cells in navigating stress and gradually restoring homeostatic equilibrium. Recent studies have unveiled the intricate connection between autophagy and breast cancer. Autophagy is a double-edged sword in breast cancer, demonstrating a dual role: restraining its onset and progression on one hand, while promoting its metastasis and advancement on the other. It is also because of this interrelationship between the two that regulation of autophagy in the treatment of breast cancer is now an important strategy in clinical treatment. In this article, we systematically survey the recent research findings, elucidating the multifaceted role of autophagy in breast cancer and its underlying mechanisms, with the aim of contributing new references to the clinical management of breast cancer.
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Affiliation(s)
- Tang Yu
- The Third Affiliated Hospital of Kunming Medical University, Kunming, China
- The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Liu Rui
- The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhao Jiumei
- Chongqing Nanchuan District People's Hospital, Chongqing, China
| | - Li Ziwei
- Chongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Hu Ying
- The Second Affiliatied Hospital of Kunming Medical University and Department of Clinical Larboratory, Kunming, China.
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Rajabi S, Shakib H, Safari-Alighiarloo N, Maresca M, Hamzeloo-Moghadam M. Targeting autophagy for breast cancer prevention and therapy: From classical methods to phytochemical agents. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:1475-1491. [PMID: 39539439 PMCID: PMC11556757 DOI: 10.22038/ijbms.2024.79405.17201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 06/02/2024] [Indexed: 11/16/2024]
Abstract
Breast cancer is a heterogeneous illness comprising diverse biological subtypes, each of which differs in incidence, response to therapies, and prognosis. Despite the presence of novel medications that effectively target vital cellular signaling pathways and their application in clinical practice, breast cancer can still develop resistance to therapies by various mechanisms. Autophagy is a conserved catabolic cellular process that maintains intracellular metabolic homeostasis by removing dysfunctional or unnecessary cellular materials to recycle cytosolic components. This process serves as an adaptive survival response to diverse stress stimuli, thereby contributing to tumor initiation, progression, and drug resistance, leading to restriction of the effectiveness of chemotherapeutic treatments. Regarding this potential role of autophagy, molecular regulation and signal transduction of this process represent an attractive approach to combat cancer development and drug resistance. Among various therapeutic agents, bioactive plant-derived compounds have received significant interest as promising anticancer drugs. A plethora of evidence has shown that phytochemicals with the capacity to modulate autophagy may have the potential to be used as inhibitors of breast cancer growth. In this review, we describe recent findings on autophagy targeting along with conventional methods for breast cancer therapy. Subsequently, we introduce phytochemical compounds with the capacity to modulate autophagy for breast cancer treatment.
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Affiliation(s)
- Sadegh Rajabi
- Traditional Medicine and Materia Medica Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Heewa Shakib
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nahid Safari-Alighiarloo
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
| | - Marc Maresca
- Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, 13013 Marseille, France
| | - Maryam Hamzeloo-Moghadam
- Traditional Medicine and Materia Medica Research Center and Department of Traditional Pharmacy, School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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8
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Buono R, Tucci J, Cutri R, Guidi N, Mangul S, Raucci F, Pellegrini M, Mittelman SD, Longo VD. Fasting-Mimicking Diet Inhibits Autophagy and Synergizes with Chemotherapy to Promote T-Cell-Dependent Leukemia-Free Survival. Cancers (Basel) 2023; 15:5870. [PMID: 38136414 PMCID: PMC10741737 DOI: 10.3390/cancers15245870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/07/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Fasting mimicking diets (FMDs) are effective in the treatment of many solid tumors in mouse models, but their effect on hematologic malignancies is poorly understood, particularly in combination with standard therapies. Here we show that cycles of a 3-day FMD given to high-fat-diet-fed mice once a week increased the efficacy of vincristine to improve survival from BCR-ABL B acute lymphoblastic leukemia (ALL). In mice fed a standard diet, FMD cycles in combination with vincristine promoted cancer-free survival. RNA seq and protein assays revealed a vincristine-dependent decrease in the expression of multiple autophagy markers, which was exacerbated by the fasting/FMD conditions. The autophagy inhibitor chloroquine could substitute for fasting/FMD to promote cancer-free survival in combination with vincristine. In vitro, targeted inhibition of autophagy genes ULK1 and ATG9a strongly potentiated vincristine's toxicity. Moreover, anti-CD8 antibodies reversed the effects of vincristine plus fasting/FMD in promoting leukemia-free survival in mice, indicating a central role of the immune system in this response. Thus, the inhibition of autophagy and enhancement of immune responses appear to be mediators of the fasting/FMD-dependent cancer-free survival in ALL mice.
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Affiliation(s)
- Roberta Buono
- Department of Biological Sciences, Longevity Institute, School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089, USA
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA
| | - Jonathan Tucci
- Center for Endocrinology, Diabetes & Metabolism, Children’s Hospital Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027, USA
| | - Raffaello Cutri
- Department of Biological Sciences, Longevity Institute, School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089, USA
| | - Novella Guidi
- Department of Biological Sciences, Longevity Institute, School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089, USA
| | - Serghei Mangul
- Department of Computer Science, University of California Los Angeles, 580 Portola Plaza, Los Angeles, CA 90095, USA
- Institute for Quantitative and Computational Biosciences, Boyer Hall, 611 Charles Young Drive, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Franca Raucci
- IFOM AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
| | - Matteo Pellegrini
- Institute for Quantitative and Computational Biosciences, Boyer Hall, 611 Charles Young Drive, University of California Los Angeles, Los Angeles, CA 90095, USA
- Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, 801 Hilgard Avenue, Los Angeles, CA 90095, USA
| | - Steven D. Mittelman
- Center for Endocrinology, Diabetes & Metabolism, Children’s Hospital Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027, USA
- Division of Pediatric Endocrinology, UCLA Mattel Children’s Hospital, 10833 Le Conte Avenue, MDCC 22-315, Los Angeles, CA 90095, USA
| | - Valter D. Longo
- Department of Biological Sciences, Longevity Institute, School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089, USA
- IFOM AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
- Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Liu C, Lu C, Yixi L, Hong J, Dong F, Ruan S, Hu T, Zhao X. Exosomal Linc00969 induces trastuzumab resistance in breast cancer by increasing HER-2 protein expression and mRNA stability by binding to HUR. Breast Cancer Res 2023; 25:124. [PMID: 37848981 PMCID: PMC10580635 DOI: 10.1186/s13058-023-01720-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 09/25/2023] [Indexed: 10/19/2023] Open
Abstract
BACKGROUND Breast cancer (BC) is the most common malignant disease in female patients worldwide. In HER-2+ BC patients, trastuzumab therapy is associated with a better prognosis. However, many HER-2+ BC patients experience recurrence or metastasis because of trastuzumab resistance. The mechanisms underlying trastuzumab resistance remain unclear. Recently, substantial evidence has suggested that exosomes are associated with drug resistance, and lncRNAs have attracted increasing attention due to their potential role in the regulation of trastuzumab resistance. METHODS We collected the exosomes from the plasma of BC patients with and without trastuzumab resistance, sequenced the whole transcriptomes, identified differentially expressed lncRNAs, and identified lncRNA Linc00969, which was overexpressed in trastuzumab-resistant patients. Then, we established trastuzumab-resistant BC cell lines and explored the role of exosomal Linc00969 in trastuzumab resistance in vitro and in vivo by silencing or overexpressing Linc00969 and performing a series of functional analyses. Furthermore, to explore the mechanism by which exosomal Linc00969 contributes to trastuzumab resistance, we measured changes in HER-2, HUR and autophagy-related protein expression levels after regulating Linc00969 expression. In addition, we investigated the interaction between Linc00969 and HUR via pull-down and RIP assays and the effect of HUR on HER-2 expression and trastuzumab resistance after blocking HUR. RESULTS We first found that exosomal lncRNA Linc00969 was overexpressed in trastuzumab-resistant BC patients and that exosome-mediated Linc00969 transfer could disseminate trastuzumab resistance in BC. Then, we found that silencing Linc00969 could reduce trastuzumab resistance and that overexpressing Linc00969 could enhance trastuzumab resistance. Furthermore, our results showed that Linc00969 could upregulate HER-2 expression at the protein level and maintain the stability of HER-2 mRNA by binding to HUR. Additionally, we found that exosomal Linc00969 could regulate trastuzumab resistance by inducing autophagy. CONCLUSIONS In this study, we first identified that exosomal lncRNA Linc00969 could induce trastuzumab resistance by increasing HER-2 protein expression and mRNA stability by binding to HUR, and Linc00969 might also be involved in trastuzumab resistance by inducing autophagy. Our results elucidate a novel mechanism underlying trastuzumab resistance, and Linc00969 might be a new target for improving the treatment of HER-2+ BC patients.
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Affiliation(s)
- Cuiwei Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chong Lu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lamu Yixi
- Tibet Shannan Maternal and Child Health Hospital, Shannan, 856000, Tibet, China
| | - Jiaxing Hong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Fang Dong
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shengnan Ruan
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Ting Hu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, 430022, China.
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Tibet Shannan Maternal and Child Health Hospital, Shannan, 856000, Tibet, China.
| | - Xiangwang Zhao
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Wu X, Huang S, He W, Song M. Emerging insights into mechanisms of trastuzumab resistance in HER2-positive cancers. Int Immunopharmacol 2023; 122:110602. [PMID: 37437432 DOI: 10.1016/j.intimp.2023.110602] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/19/2023] [Accepted: 07/02/2023] [Indexed: 07/14/2023]
Abstract
HER2 is an established therapeutic target in breast, gastric, and gastroesophageal junction carcinomas with HER2 overexpression or genomic alterations. The humanized monoclonal antibody trastuzumab targeting HER2 has substantially improved the clinical outcomes of HER2-positive patients, yet the inevitable intrinsic or acquired resistance to trastuzumab limits its clinical benefit, necessitating the elucidation of resistance mechanisms to develop alternate therapeutic strategies. This review presents an overview of trastuzumab resistance mechanisms involving signaling pathways, cellular metabolism, cell plasticity, and tumor microenvironment, particularly discussing the prospects of developing rational combinations to improve patient outcomes.
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Affiliation(s)
- Xiaoxue Wu
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
| | - Shuting Huang
- School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Weiling He
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Department of Gastrointestinal Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361000, China.
| | - Mei Song
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
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11
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Franco YL, Khan C, Ait-Oudhia S. Pharmacodynamic Modeling Identifies Synergistic Interaction Between Chloroquine and Trastuzumab in Refractory HER2- positive Breast Cancer Cells. CANCER DIAGNOSIS & PROGNOSIS 2023; 3:175-182. [PMID: 36875304 PMCID: PMC9949542 DOI: 10.21873/cdp.10198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 12/09/2022] [Indexed: 03/07/2023]
Abstract
BACKGROUND/AIM Despite improvements in HER2-positive breast cancer (BC) patients' outcomes with trastuzumab, the occurrence of intrinsic or acquired resistance presents a clinical challenge. Here, we quantitatively assess the combinatorial effects of chloroquine, an autophagy inhibitor, with trastuzumab on JIMT-1 cells, a HER2-positive BC cell-line primarily resistant to trastuzumab. MATERIALS AND METHODS The temporal changes in JIMT-1 cellular viability were assessed using the CCK-8 kit, where JIMT-1 cells were exposed for 72-h to trastuzumab (0.007-17.19 μM) or chloroquine (5-50 μM) as single-agents, in combination (trastuzumab: 0.007-0.688 μM; chloroquine: 5-15 μM), or control (no drug). Concentration-response relationships were built for each treatment arm to determine drugs' concentrations inducing 50% of cell-killing (IC50). Cellular pharmacodynamic models were built to characterize the time-trajectory of JIMT-1 cellular viability under each treatment arm. The nature of trastuzumab and chloroquine interaction was quantified by estimating the interaction parameter (Ψ). RESULTS The IC50 were estimated at 19.7 and 24.4 μM for trastuzumab and chloroquine. The maximum killing effect was about thrice higher for chloroquine than trastuzumab (0.0405 vs. 0.0125 h-1), validating chloroquine's superior anti-cancer effect on JIMT-1 cells compared to trastuzumab. The time-delay for chloroquine cell-killing was twice longer than that for trastuzumab (17.7 vs. 7 h), suggesting a chloroquine time-dependent anti-cancer effect. The Ψ was determined at 0.529 (Ψ<1), indicating a synergistic interaction. CONCLUSION This proof-of-concept study on JIMT-1 cells identified chloroquine and trastuzumab synergistic interaction, warranting further in vivo investigations.
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Affiliation(s)
- Yesenia L Franco
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida, College of Pharmacy, Orlando, FL, U.S.A
| | - Christine Khan
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida, College of Pharmacy, Orlando, FL, U.S.A
| | - Sihem Ait-Oudhia
- Quantitative Pharmacology and Pharmacometrics (QP2), Merck & Co., Inc, Kenilworth, NJ, U.S.A
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12
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Giannopoulos S, Bozkus CC, Zografos E, Athanasiou A, Bongiovanni AM, Doulaveris G, Bakoyiannis CN, Theodoropoulos GE, Zografos GC, Witkin SS, Orfanelli T. Targeting Both Autophagy and Immunotherapy in Breast Cancer Treatment. Metabolites 2022; 12:metabo12100966. [PMID: 36295867 PMCID: PMC9607060 DOI: 10.3390/metabo12100966] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/30/2022] [Accepted: 10/04/2022] [Indexed: 11/16/2022] Open
Abstract
As clinical efforts towards breast-conserving therapy and prolonging survival of those with metastatic breast cancer increase, innovative approaches with the use of biologics are on the rise. Two areas of current focus are cancer immunotherapy and autophagy, both of which have been well-studied independently but have recently been shown to have intertwining roles in cancer. An increased understanding of their interactions could provide new insights that result in novel diagnostic, prognostic, and therapeutic strategies. In this breast cancer-focused review, we explore the interactions between autophagy and two clinically relevant immune checkpoint pathways; the programmed cell death-1 receptor with its ligand (PD-L1)/PD-1 and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)/CD80 and CD86 (B7-1 and B7-2). Furthermore, we discuss emerging preclinical and clinical data supporting targeting both immunotherapy and autophagy pathway manipulation as a promising approach in the treatment of breast cancer.
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Affiliation(s)
- Spyridon Giannopoulos
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Cansu Cimen Bozkus
- Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA
| | - Eleni Zografos
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
| | - Aikaterini Athanasiou
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Ann Marie Bongiovanni
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Georgios Doulaveris
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Chris N Bakoyiannis
- First Department of Surgery, Division of Vascular Surgery, Laikon General Hospital, National Kapodistrian University of Athens, 15772 Athens, Greece
| | - Georgios E Theodoropoulos
- First Department of Propaedeutic Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
| | - Georgios C Zografos
- First Department of Propaedeutic Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
| | - Steven S Witkin
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Theofano Orfanelli
- First Department of Propaedeutic Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
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13
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Gámez-Chiachio M, Molina-Crespo Á, Ramos-Nebot C, Martinez-Val J, Martinez L, Gassner K, Llobet FJ, Soriano M, Hernandez A, Cordani M, Bernadó-Morales C, Diaz E, Rojo-Sebastian A, Triviño JC, Sanchez L, Rodríguez-Barrueco R, Arribas J, Llobet-Navás D, Sarrió D, Moreno-Bueno G. Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation. J Exp Clin Cancer Res 2022; 41:285. [PMID: 36163066 PMCID: PMC9511784 DOI: 10.1186/s13046-022-02497-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 09/19/2022] [Indexed: 11/10/2022] Open
Abstract
Background Gasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing resistance to therapy. Decoding the molecular mechanism of GSDMB-mediated drug resistance is crucial to identify novel effective targeted treatments for HER2/GSDMB aggressive tumors. Methods Different in vitro approaches (immunoblot, qRT-PCR, flow cytometry, proteomic analysis, immunoprecipitation, and confocal/electron microscopy) were performed in HER2 breast and gastroesophageal carcinoma cell models. Results were then validated using in vivo preclinical animal models and analyzing human breast and gastric cancer samples. Results GSDMB up-regulation renders HER2 cancer cells more resistant to anti-HER2 agents by promoting protective autophagy. Accordingly, the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response of GSDMB-positive cancers in vitro and in zebrafish and mice tumor xenograft in vivo models. Mechanistically, GSDMB N-terminal domain interacts with the key components of the autophagy machinery LC3B and Rab7, facilitating the Rab7 activation during pro-survival autophagy in response to anti-HER2 therapies. Finally, we validated these results in clinical samples where GSDMB/Rab7/LC3B co-expression associates significantly with relapse in HER2 breast and gastric cancers. Conclusion Our findings uncover for the first time a functional link between GSDMB over-expression and protective autophagy in response to HER2-targeted therapies. GSDMB behaves like an autophagy adaptor and plays a pivotal role in modulating autophagosome maturation through Rab7 activation. Finally, our results provide a new and accessible therapeutic approach for HER2/GSDMB + cancers with adverse clinical outcome. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02497-w.
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14
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Gámez-Chiachio M, Sarrió D, Moreno-Bueno G. Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs. Cancers (Basel) 2022; 14:4543. [PMID: 36139701 PMCID: PMC9496705 DOI: 10.3390/cancers14184543] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/09/2022] [Accepted: 09/15/2022] [Indexed: 11/17/2022] Open
Abstract
The prognosis and quality of life of HER2 breast cancer patients have significantly improved due to the crucial clinical benefit of various anti-HER2 targeted therapies. However, HER2 tumors can possess or develop several resistance mechanisms to these treatments, thus leaving patients with a limited set of additional therapeutic options. Fortunately, to overcome this problem, in recent years, multiple different and complementary approaches have been developed (such as antibody-drug conjugates (ADCs)) that are in clinical or preclinical stages. In this review, we focus on emerging strategies other than on ADCs that are either aimed at directly target the HER2 receptor (i.e., novel tyrosine kinase inhibitors) or subsequent intracellular signaling (e.g., PI3K/AKT/mTOR, CDK4/6 inhibitors, etc.), as well as on innovative approaches designed to attack other potential tumor weaknesses (such as immunotherapy, autophagy blockade, or targeting of other genes within the HER2 amplicon). Moreover, relevant technical advances such as anti-HER2 nanotherapies and immunotoxins are also discussed. In brief, this review summarizes the impact of novel therapeutic approaches on current and future clinical management of aggressive HER2 breast tumors.
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Affiliation(s)
- Manuel Gámez-Chiachio
- Biochemistry Department, Medicine Faculty, Universidad Autónoma Madrid-CSIC, IdiPaz, 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red-Oncología (CIBERONC), 28029 Madrid, Spain
| | - David Sarrió
- Biochemistry Department, Medicine Faculty, Universidad Autónoma Madrid-CSIC, IdiPaz, 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red-Oncología (CIBERONC), 28029 Madrid, Spain
| | - Gema Moreno-Bueno
- Biochemistry Department, Medicine Faculty, Universidad Autónoma Madrid-CSIC, IdiPaz, 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red-Oncología (CIBERONC), 28029 Madrid, Spain
- MD Anderson International Foundation, 28033 Madrid, Spain
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15
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Menendez JA, Lupu R. Fatty acid synthase: A druggable driver of breast cancer brain metastasis. Expert Opin Ther Targets 2022; 26:427-444. [PMID: 35545806 DOI: 10.1080/14728222.2022.2077189] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Brain metastasis (BrM) is a key contributor to morbidity and mortality in breast cancer patients, especially among high-risk epidermal growth factor receptor 2-positive (HER2+) and triple-negative/basal-like molecular subtypes. Optimal management of BrM is focused on characterizing a "BrM dependency map" to prioritize targetable therapeutic vulnerabilities. AREAS COVERED We review recent studies addressing the targeting of BrM in the lipid-deprived brain environment, which selects for brain-tropic breast cancer cells capable of cell-autonomously generating fatty acids by upregulating de novo lipogenesis via fatty acid synthase (FASN). Disruption of FASN activity impairs breast cancer growth in the brain, but not extracranially, and mapping of the molecular causes of organ-specific patterns of metastasis has uncovered an enrichment of lipid metabolism signatures in brain metastasizing cells. Targeting SREBP1-the master regulator of lipogenic gene transcription-curtails the ability of breast cancer cells to survive in the brain microenvironment. EXPERT OPINION Targeting FASN represents a new therapeutic opportunity for patients with breast cancer and BrM. Delivery of brain-permeable FASN inhibitors and identifying strategies to target metabolic plasticity that might compensate for impaired brain FASN activity are two potential roadblocks that may hinder FASN-centered strategies against BrM.
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Affiliation(s)
- Javier A Menendez
- Metabolism and Cancer Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17007 Girona, Spain.,Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain
| | - Ruth Lupu
- Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN 55905, USA.,Department of Biochemistry and Molecular Biology Laboratory, Mayo Clinic Minnesota, Rochester, MN 55905, USA.,Mayo Clinic Cancer Center, Rochester, MN 55905, USA
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16
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Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress. Cells 2022; 11:cells11050851. [PMID: 35269473 PMCID: PMC8909305 DOI: 10.3390/cells11050851] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/17/2022] [Accepted: 02/22/2022] [Indexed: 02/07/2023] Open
Abstract
In response to environmental stimuli, cells make a series of adaptive changes to combat the injury, repair the damage, and increase the tolerance to the stress. However, once the damage is too serious to repair, the cells will undergo apoptosis to protect the overall cells through suicidal behavior. Upon external stimulation, some intracellular proteins turn into unfolded or misfolded protein, exposing their hydrophobic regions to form protein aggregation, which may ultimately produce serious damage to the cells. Ubiquitin plays an important role in the degradation of these unnatural proteins by tagging with ubiquitin chains in the ubiquitin-proteasome or autophagy system. If the two processes fail to eliminate the abnormal protein aggregates, the cells will move to apoptosis and death. Dysregulation of ubiquitin-proteasome system (UPS) and autophagy may result in the development of numerous diseases. This review focuses on the molecular mechanisms of UPS and autophagy in clearance of intracellular protein aggregates, and the relationship between dysregulation of ubiquitin network and diseases.
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17
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Takhsha FS, Vangestel C, Tanc M, De Bruycker S, Berg M, Pintelon I, Stroobants S, De Meyer GRY, Van Der Veken P, Martinet W. ATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma. Front Oncol 2021; 11:750259. [PMID: 34868951 PMCID: PMC8637338 DOI: 10.3389/fonc.2021.750259] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/12/2021] [Indexed: 01/02/2023] Open
Abstract
Resistance against anti-cancer therapy is one of the major challenges during treatment of multiple cancers. Gemcitabine is a standard first-line chemotherapeutic drug, yet autophagy is highly activated in the hypoxic microenvironment of solid tumors and enhances the survival of tumor cells against gemcitabine chemotherapy. Recently, we showed the add-on effect of autophagy inhibitor UAMC-2526 to prevent HT-29 colorectal tumor growth in CD1-/- Foxn1nu mice treated with oxaliplatin. In this study, we aimed to investigate the potential beneficial effects of UAMC-2526 in a syngeneic Panc02 mouse model of pancreatic ductal adenocarcinoma (PDAC). Our data showed that UAMC-2526 combined with gemcitabine significantly reduced tumor growth as compared to the individual treatments. However, in contrast to in vitro experiments with Panc02 cells in culture, we were unable to detect autophagy inhibition by UAMC-2526 in Panc02 tumor tissue, neither via western blot analysis of autophagy markers LC3 and p62, nor by transmission electron microscopy. In vitro experiments revealed that UAMC-2526 enhances the potential of gemcitabine to inhibit Panc02 cell proliferation without obvious induction of cell death. Altogether, we conclude that although the combination treatment of UAMC-2526 with gemcitabine did not inhibit autophagy in the Panc02 mouse model, it has a beneficial effect on tumor growth inhibition.
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Affiliation(s)
| | - Christel Vangestel
- Molecular Imaging Center Antwerp (MICA), University of Antwerp, Antwerp, Belgium.,Department of Nuclear Medicine, University Hospital Antwerp, Edegem, Belgium
| | - Muhammet Tanc
- Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.,Department of Imaging Chemistry & Biology, King's College London, London, United Kingdom
| | - Sven De Bruycker
- Molecular Imaging Center Antwerp (MICA), University of Antwerp, Antwerp, Belgium.,Department of Science and Technology, AP University of Applied Sciences and Arts Antwerp, Antwerp, Belgium
| | - Maya Berg
- Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium
| | - Isabel Pintelon
- Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium
| | - Sigrid Stroobants
- Molecular Imaging Center Antwerp (MICA), University of Antwerp, Antwerp, Belgium.,Department of Nuclear Medicine, University Hospital Antwerp, Edegem, Belgium
| | - Guido R Y De Meyer
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.,Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium
| | - Pieter Van Der Veken
- Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.,Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium
| | - Wim Martinet
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.,Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium
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18
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Zhao Z, Wan J, Guo M, Yang Z, Li Z, Wang Y, Ming L. Long non-coding RNA LINC01559 exerts oncogenic role via enhancing autophagy in lung adenocarcinoma. Cancer Cell Int 2021; 21:624. [PMID: 34823534 PMCID: PMC8614059 DOI: 10.1186/s12935-021-02338-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 11/12/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) have been verified to play fatal role in regulating the progression of lung adenocarcinoma (LUAD). Although lncRNAs play important role in regulating the autophagy of tumor cells, the function and molecular mechanism of LINC01559 in regulating lung cancer development remain to be elucidated. METHOD AND MATERIALS In this study, we used bioinformatics to screen out autophagy-related lncRNAs from TCGA-LUAD repository. Then the least absolute shrinkage and selection operator (LASSO) regression was applied to establish the signature of autophagy-related lncRNAs so that clinical characteristics and survival in LUAD patients be evaluated. Finally, we selected the most significant differences lncRNA, LINC01559, to verify its function in regulating LUAD progression in vitro. RESULTS We found high expression of LINC01559 indicates lymph node metastasis and poor prognosis. Besides, LINC01559 promotes lung cancer cell proliferation and migration in vitro, by enhancing autophagy signal pathway via sponging hsa-miR-1343-3p. CONCLUSION We revealed a novel prognostic model based on autophagy-related lncRNAs, and provide a new therapeutic target and for patients with lung adenocarcinoma named LINC01559.
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Affiliation(s)
- Zhuochen Zhao
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University and the Key Clinical Laboratory of Henan Province, Henan, China
| | - Junhu Wan
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University and the Key Clinical Laboratory of Henan Province, Henan, China
| | - Manman Guo
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University and the Key Clinical Laboratory of Henan Province, Henan, China
| | - Zhengwu Yang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University and the Key Clinical Laboratory of Henan Province, Henan, China
| | - Zhuofang Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University and the Key Clinical Laboratory of Henan Province, Henan, China
| | - Yangxia Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University and the Key Clinical Laboratory of Henan Province, Henan, China
| | - Liang Ming
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University and the Key Clinical Laboratory of Henan Province, Henan, China.
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19
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Ganzleben I, Neurath MF, Becker C. Autophagy in Cancer Therapy-Molecular Mechanisms and Current Clinical Advances. Cancers (Basel) 2021; 13:cancers13215575. [PMID: 34771737 PMCID: PMC8583685 DOI: 10.3390/cancers13215575] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/27/2021] [Accepted: 11/05/2021] [Indexed: 01/18/2023] Open
Abstract
Simple Summary Autophagy is the capability of cells to dismantle and recycle parts of themselves. This process is closely intertwined with other crucial cell functions, such as growth and control of metabolism. Autophagy is oftentimes dysregulated in cancer and offers established and advanced tumors protection against a lack of nutrients and an advantage regarding proliferation. This review will present an overview of the basics of human autophagy, its dysregulation in cancer, and approaches to target autophagy in cancer treatment in recent and current clinical trials as well as new findings of preclinical research. 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 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.
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Affiliation(s)
- Ingo Ganzleben
- Department of Medicine 1, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (I.G.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (I.G.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Christoph Becker
- Department of Medicine 1, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (I.G.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), Universitätsklinikum Erlangen, 91054 Erlangen, Germany
- Correspondence:
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20
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Niklaus NJ, Tokarchuk I, Zbinden M, Schläfli AM, Maycotte P, Tschan MP. The Multifaceted Functions of Autophagy in Breast Cancer Development and Treatment. Cells 2021; 10:cells10061447. [PMID: 34207792 PMCID: PMC8229352 DOI: 10.3390/cells10061447] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/04/2021] [Accepted: 06/04/2021] [Indexed: 12/12/2022] Open
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 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.
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Affiliation(s)
- Nicolas J. Niklaus
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
- Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland
| | - Igor Tokarchuk
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
- Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland
| | - Mara Zbinden
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
| | - Anna M. Schläfli
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
| | - Paola Maycotte
- Centro de Investigación Biomédica de Oriente (CIBIOR), Instituto Mexicano del Seguro Social (IMSS), Puebla 74360, Mexico;
| | - Mario P. Tschan
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
- Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland
- Correspondence: ; Tel.: +41-31-632-87-80
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21
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Chmurska A, Matczak K, Marczak A. Two Faces of Autophagy in the Struggle against Cancer. Int J Mol Sci 2021; 22:2981. [PMID: 33804163 PMCID: PMC8000091 DOI: 10.3390/ijms22062981] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/10/2021] [Accepted: 03/12/2021] [Indexed: 12/12/2022] Open
Abstract
Autophagy can play a double role in cancerogenesis: it can either inhibit further development of the disease or protect cells, causing stimulation of tumour growth. This phenomenon is called "autophagy paradox", and is characterised by the features that the autophagy process provides the necessary substrates for biosynthesis to meet the cell's energy needs, and that the over-programmed activity of this process can lead to cell death through apoptosis. The fight against cancer is a difficult process due to high levels of resistance to chemotherapy and radiotherapy. More and more research is indicating that autophagy may play a very important role in the development of resistance by protecting cancer cells, which is why autophagy in cancer therapy can act as a "double-edged sword". This paper attempts to analyse the influence of autophagy and cancer stem cells on tumour development, and to compare new therapeutic strategies based on the modulation of these processes.
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Affiliation(s)
- Anna Chmurska
- Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland
| | - Karolina Matczak
- Department of Medical Biophysics, Faculty of Biology and Environmental Protection, Institute of Biophysics, University of Lodz, Pomorska Street 141/143, 90-236 Lodz, Poland; (K.M.); (A.M.)
| | - Agnieszka Marczak
- Department of Medical Biophysics, Faculty of Biology and Environmental Protection, Institute of Biophysics, University of Lodz, Pomorska Street 141/143, 90-236 Lodz, Poland; (K.M.); (A.M.)
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22
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Patel NH, Bloukh S, Alwohosh E, Alhesa A, Saleh T, Gewirtz DA. Autophagy and senescence in cancer therapy. Adv Cancer Res 2021; 150:1-74. [PMID: 33858594 DOI: 10.1016/bs.acr.2021.01.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Tumor cells can undergo diverse responses to cancer therapy. While apoptosis represents the most desirable outcome, tumor cells can alternatively undergo autophagy and senescence. Both autophagy and senescence have the potential to make complex contributions to tumor cell survival via both cell autonomous and cell non-autonomous pathways. The induction of autophagy and senescence in tumor cells, preclinically and clinically, either individually or concomitantly, has generated interest in the utilization of autophagy modulating and senolytic therapies to target autophagy and senescence, respectively. This chapter summarizes the current evidence for the promotion of autophagy and senescence as fundamental responses to cancer therapy and discusses the complexity of their functional contributions to cell survival and disease outcomes. We also highlight current modalities designed to exploit autophagy and senescence in efforts to improve the efficacy of cancer therapy.
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Affiliation(s)
- Nipa H Patel
- Department of Pharmacology and Toxicology and Medicine, Virginia Commonwealth University, Richmond, VA, United States; Massey Cancer Center, Goodwin Research Laboratories, Virginia Commonwealth University, Richmond, VA, United States
| | - Sarah Bloukh
- Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | - Enas Alwohosh
- Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | - Ahmad Alhesa
- Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | - Tareq Saleh
- Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | - David A Gewirtz
- Department of Pharmacology and Toxicology and Medicine, Virginia Commonwealth University, Richmond, VA, United States; Massey Cancer Center, Goodwin Research Laboratories, Virginia Commonwealth University, Richmond, VA, United States.
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23
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Xiao M, Benoit A, Hasmim M, Duhem C, Vogin G, Berchem G, Noman MZ, Janji B. Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies. Front Oncol 2021; 11:626309. [PMID: 33718194 PMCID: PMC7951055 DOI: 10.3389/fonc.2021.626309] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 01/15/2021] [Indexed: 12/21/2022] Open
Abstract
Autophagy is a highly regulated multi-step process that occurs at the basal level in almost all cells. Although the deregulation of the autophagy process has been described in several pathologies, the role of autophagy in cancer as a cytoprotective mechanism is currently well established and supported by experimental and clinical evidence. Our understanding of the molecular mechanism of the autophagy process has largely contributed to defining how we can harness this process to improve the benefit of cancer therapies. While the role of autophagy in tumor resistance to chemotherapy is extensively documented, emerging data point toward autophagy as a mechanism of cancer resistance to radiotherapy, targeted therapy, and immunotherapy. Therefore, manipulating autophagy has emerged as a promising strategy to overcome tumor resistance to various anti-cancer therapies, and autophagy modulators are currently evaluated in combination therapies in several clinical trials. In this review, we will summarize our current knowledge of the impact of genetically and pharmacologically modulating autophagy genes and proteins, involved in the different steps of the autophagy process, on the therapeutic benefit of various cancer therapies. We will also briefly discuss the challenges and limitations to developing potent and selective autophagy inhibitors that could be used in ongoing clinical trials.
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Affiliation(s)
- Malina Xiao
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg
| | - Alice Benoit
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg
| | - Meriem Hasmim
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg
| | - Caroline Duhem
- Department of Hemato-oncology, Centre Hospitalier du Luxembourg, Luxembourg City, Luxembourg
| | - Guillaume Vogin
- Université de Lorraine - UMR 7365, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Vandoeuvre-lès-Nancy, France.,Centre François Baclesse, Esch-sur-Alzette, Luxembourg
| | - Guy Berchem
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg.,Department of Hemato-oncology, Centre Hospitalier du Luxembourg, Luxembourg City, Luxembourg
| | - Muhammad Zaeem Noman
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg
| | - Bassam Janji
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg
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24
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Ho CY, Chang AC, Hsu CH, Tsai TF, Lin YC, Chou KY, Chen HE, Lin JF, Chen PC, Hwang TIS. Miconazole induces protective autophagy in bladder cancer cells. ENVIRONMENTAL TOXICOLOGY 2021; 36:185-193. [PMID: 32981224 DOI: 10.1002/tox.23024] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 07/17/2020] [Accepted: 08/28/2020] [Indexed: 06/11/2023]
Abstract
Autophagy plays a dual function in cancer progression; autophagy activation can support cancer cell survival or contribute to cell death. Miconazole, a Food and Drug Administration-approved antifungal drug, has been implicated in oncology research recently. Miconazole was found to exert antitumor effects in various tumors, including bladder cancer (BC). However, whether it provokes protective autophagy has been never discussed. We provide evidence that miconazole induces protective autophagy in BC for the first time. The results indicated that 1A/1B-light chain 3 (LC3)-II processing and p62 expression were elevated after miconazole exposure. Also, adenosine monophosphate-activated protein kinase phosphorylation was increased after miconazole treatment. We also confirmed the autophagy-promoting effect of miconazole in the presence of bafilomycin A1 (Baf A1). The result indicates that a combination treatment of miconazole and Baf A1 improved LC3-II processing, confirming that miconazole promoted autophagic flux. The acridine orange, Lysotracker, and cathepsin D staining results indicate that miconazole increased lysosome formation, revealing its autophagy-promoting function. Finally, miconazole and autophagy inhibitor 3-methyladenine cotreatment further reduced the cell viability and induced apoptosis in BC cells, proving that miconazole provokes protective autophagy in BC cells. Our findings approve that miconazole has an antitumor effect in promoting cell apoptosis; however, its function of protective autophagy is needed to be concerned in cancer treatment.
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Affiliation(s)
- Chao-Yen Ho
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - An-Chen Chang
- Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Chung-Hua Hsu
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Te-Fu Tsai
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
| | - Yi-Chia Lin
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
| | - Kuang-Yu Chou
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
| | - Hung-En Chen
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Ji-Fan Lin
- Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Po-Chun Chen
- Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Thomas I-Sheng Hwang
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
- Department of Urology, Taipei Medical University, Taipei, Taiwan
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25
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Hao M, Yeo SK, Turner K, Harold A, Yang Y, Zhang X, Guan JL. Autophagy Blockade Limits HER2+ Breast Cancer Tumorigenesis by Perturbing HER2 Trafficking and Promoting Release Via Small Extracellular Vesicles. Dev Cell 2021; 56:341-355.e5. [PMID: 33472043 DOI: 10.1016/j.devcel.2020.12.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 11/05/2020] [Accepted: 12/18/2020] [Indexed: 01/04/2023]
Abstract
Autophagy modulation is an emerging strategy for cancer therapy. By deleting an essential autophagy gene or disrupting its autophagy function, we determined a mechanism of HER2+ breast cancer tumorigenesis by directly regulating the oncogenic driver. Disruption of FIP200-mediated autophagy reduced HER2 expression on the tumor cell surface and abolished mammary tumorigenesis in MMTV-Neu mice. Decreased HER2 surface expression was due to trafficking from the Golgi to the endocytic pathways instead of the plasma membrane. Autophagy inhibition led to HER2 accumulation in early and late endosomes associated with intraluminal vesicles and released from tumor cells in small extracellular vesicles (sEVs). Increased HER2 release from sEVs correlated with reduced tumor cell surface levels. Blocking sEVs secretion rescued HER2 levels in tumor cells. Our results demonstrate a role for autophagy to promote tumorigenesis in HER2+ breast cancer. This suggests that blocking autophagy could supplement current anti-HER2 agents for treating the disease.
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Affiliation(s)
- Mingang Hao
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Syn Kok Yeo
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Kevin Turner
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Alexis Harold
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Yongguang Yang
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Xiaoting Zhang
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Jun-Lin Guan
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
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26
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Chern YJ, Tai IT. Adaptive response of resistant cancer cells to chemotherapy. Cancer Biol Med 2020; 17:842-863. [PMID: 33299639 PMCID: PMC7721100 DOI: 10.20892/j.issn.2095-3941.2020.0005] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 04/27/2020] [Indexed: 12/13/2022] Open
Abstract
Despite advances in cancer therapeutics and the integration of personalized medicine, the development of chemoresistance in many patients remains a significant contributing factor to cancer mortality. Upon treatment with chemotherapeutics, the disruption of homeostasis in cancer cells triggers the adaptive response which has emerged as a key resistance mechanism. In this review, we summarize the mechanistic studies investigating the three major components of the adaptive response, autophagy, endoplasmic reticulum (ER) stress signaling, and senescence, in response to cancer chemotherapy. We will discuss the development of potential cancer therapeutic strategies in the context of these adaptive resistance mechanisms, with the goal of stimulating research that may facilitate the development of effective cancer therapy.
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Affiliation(s)
- Yi-Jye Chern
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia V5Z1L3, Canada.,Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver, British Columbia V5Z1L3, Canada
| | - Isabella T Tai
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia V5Z1L3, Canada.,Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver, British Columbia V5Z1L3, Canada
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27
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Targeting autophagy to overcome drug resistance: further developments. J Hematol Oncol 2020; 13:159. [PMID: 33239065 PMCID: PMC7687716 DOI: 10.1186/s13045-020-01000-2] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 11/15/2020] [Indexed: 12/13/2022] Open
Abstract
Inhibiting cell survival and inducing cell death are the main approaches of tumor therapy. Autophagy plays an important role on intracellular metabolic homeostasis by eliminating dysfunctional or unnecessary proteins and damaged or aged cellular organelles to recycle their constituent metabolites that enable the maintenance of cell survival and genetic stability and even promotes the drug resistance, which severely limits the efficacy of chemotherapeutic drugs. Currently, targeting autophagy has a seemingly contradictory effect to suppress and promote tumor survival, which makes the effect of targeting autophagy on drug resistance more confusing and fuzzier. In the review, we summarize the regulation of autophagy by emerging ways, the action of targeting autophagy on drug resistance and some of the new therapeutic approaches to treat tumor drug resistance by interfering with autophagy-related pathways. The full-scale understanding of the tumor-associated signaling pathways and physiological functions of autophagy will hopefully open new possibilities for the treatment of tumor drug resistance and the improvement in clinical outcomes.
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28
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Cozzo AJ, Coleman MF, Pearce JB, Pfeil AJ, Etigunta SK, Hursting SD. Dietary Energy Modulation and Autophagy: Exploiting Metabolic Vulnerabilities to Starve Cancer. Front Cell Dev Biol 2020; 8:590192. [PMID: 33224954 PMCID: PMC7674637 DOI: 10.3389/fcell.2020.590192] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/14/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer cells experience unique and dynamic shifts in their metabolic function in order to survive, proliferate, and evade growth inhibition in the resource-scarce tumor microenvironment. Therefore, identification of pharmacological agents with potential to reprogram cancer cell metabolism may improve clinical outcomes in cancer therapy. Cancer cells also often exhibit an increased dependence on the process known as autophagy, both for baseline survival and as a response to stressors such as chemotherapy or a decline in nutrient availability. There is evidence to suggest that this increased dependence on autophagy in cancer cells may be exploitable clinically by combining autophagy modulators with existing chemotherapies. In light of the increased metabolic rate in cancer cells, interest is growing in approaches aimed at "starving" cancer through dietary and pharmacologic interventions that reduce availability of nutrients and pro-growth hormonal signals known to promote cancer progression. Several dietary approaches, including chronic calorie restriction and multiple forms of fasting, have been investigated for their potential anti-cancer benefits, yielding promising results in animal models. Induction of autophagy in response to dietary energy restriction may underlie some of the observed benefit. However, while interventions based on dietary energy restriction have demonstrated safety in clinical trials, uncertainty remains regarding translation to humans as well as feasibility of achieving compliance due to the potential discomfort and weight loss that accompanies dietary restriction. Further induction of autophagy through dietary or pharmacologic metabolic reprogramming interventions may enhance the efficacy of autophagy inhibition in the context of adjuvant or neo-adjuvant chemotherapy. Nonetheless, it remains unclear whether therapeutic agents aimed at autophagy induction, autophagy inhibition, or both are a viable therapeutic strategy for improving cancer outcomes. This review discusses the literature available for the therapeutic potential of these approaches.
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Affiliation(s)
- Alyssa J Cozzo
- Department of Nutrition, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Duke University School of Medicine, Durham, NC, United States
| | - Michael F Coleman
- Department of Nutrition, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jane B Pearce
- Department of Nutrition, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Alexander J Pfeil
- Department of Nutrition, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Suhas K Etigunta
- Department of Nutrition, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Stephen D Hursting
- Department of Nutrition, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Nutrition Research Institute, The University of North Carolina at Chapel Hill, Kannapolis, NC, United States
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29
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Tyutyunyk-Massey L, Gewirtz DA. Roles of autophagy in breast cancer treatment: Target, bystander or benefactor. Semin Cancer Biol 2020; 66:155-162. [DOI: 10.1016/j.semcancer.2019.11.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 11/21/2019] [Accepted: 11/29/2019] [Indexed: 12/11/2022]
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30
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Pecoraro A, Pagano M, Russo G, Russo A. Role of Autophagy in Cancer Cell Response to Nucleolar and Endoplasmic Reticulum Stress. Int J Mol Sci 2020; 21:ijms21197334. [PMID: 33020404 PMCID: PMC7582989 DOI: 10.3390/ijms21197334] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 09/29/2020] [Accepted: 10/01/2020] [Indexed: 12/15/2022] Open
Abstract
Eukaryotic cells are exposed to many internal and external stimuli that affect their fate. In particular, the exposure to some of these stimuli induces stress triggering a variety of stress responses aimed to re-establish cellular homeostasis. It is now established that the deregulation of stress response pathways plays a central role in cancer initiation and progression, allowing the adaptation of cells to an altered state in the new environment. Autophagy is a tightly regulated pathway which exerts “housekeeping” role in physiological processes. Recently, a growing amount of evidence highlighted the crucial role of autophagy in the regulation of integrated stress responses, including nucleolar and endoplasmic reticulum. In this review, we attempt to afford an overview of the complex role of nucleolar and endoplasmic reticulum stress-response mechanisms in the regulation of autophagy in cancer and cancer treatment.
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Affiliation(s)
| | | | - Giulia Russo
- Correspondence: (G.R.); (A.R.); Tel.: +39-081-678415 (G.R.); +39-081-678414 (A.R.)
| | - Annapina Russo
- Correspondence: (G.R.); (A.R.); Tel.: +39-081-678415 (G.R.); +39-081-678414 (A.R.)
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31
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Dinić J, Efferth T, García-Sosa AT, Grahovac J, Padrón JM, Pajeva I, Rizzolio F, Saponara S, Spengler G, Tsakovska I. Repurposing old drugs to fight multidrug resistant cancers. Drug Resist Updat 2020; 52:100713. [PMID: 32615525 DOI: 10.1016/j.drup.2020.100713] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/04/2020] [Accepted: 06/06/2020] [Indexed: 02/08/2023]
Abstract
Overcoming multidrug resistance represents a major challenge for cancer treatment. In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore- and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, pro-apoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations.
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Affiliation(s)
- Jelena Dinić
- Department of Neurobiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
| | | | - Jelena Grahovac
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
| | - José M Padrón
- BioLab, Instituto Universitario de Bio-Orgánica Antonio González (IUBO AG), Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez 2, E-38071 La Laguna, Spain.
| | - Ilza Pajeva
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 105, 1113 Sofia, Bulgaria
| | - Flavio Rizzolio
- Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, 301724 Venezia-Mestre, Italy; Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | - Simona Saponara
- Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - Gabriella Spengler
- Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, H-6720 Szeged, Dóm tér 10, Hungary
| | - Ivanka Tsakovska
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 105, 1113 Sofia, Bulgaria
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32
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Tumors Responsive to Autophagy-Inhibition: Identification and Biomarkers. Cancers (Basel) 2020; 12:cancers12092463. [PMID: 32878084 PMCID: PMC7563256 DOI: 10.3390/cancers12092463] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/25/2020] [Accepted: 08/27/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Although the principle of personalized medicine has been the focus of attention, many cancer therapies are still based on a one-size-fits-all approach. The same holds true for targeting cancer cell survival mechanism that allows cancer cells to recycle their constituents (autophagy). In the past several indicators of elevated dependence of cancer cells on autophagy have been described. Addition of autophagy-inhibiting agents could be beneficial in treatment of these tumors. The biomarkers and mechanisms that lead to elevated dependence on autophagy are reviewed in the current manuscript. Abstract Recent advances in cancer treatment modalities reveal the limitations of the prevalent “one-size-fits-all” therapies and emphasize the necessity to develop personalized approaches. In this perspective, identification of predictive biomarkers and intrinsic vulnerabilities are an important advancement for further therapeutic strategies. Autophagy is an important lysosomal degradation and recycling pathway that provides energy and macromolecular precursors to maintain cellular homeostasis. Although all cells require autophagy, several genetic and/or cellular changes elevate the dependence of cancer cells on autophagy for their survival and indicates that autophagy inhibition in these tumors could provide a favorable addition to current therapies. In this context, we review the current literature on tumor (sub)types with elevated dependence on autophagy for their survival and highlight an exploitable vulnerability. We provide an inventory of microenvironmental factors, genetic alterations and therapies that may be exploited with autophagy-targeted approaches to improve efficacy of conventional anti-tumor therapies.
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33
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Mele L, Del Vecchio V, Liccardo D, Prisco C, Schwerdtfeger M, Robinson N, Desiderio V, Tirino V, Papaccio G, La Noce M. The role of autophagy in resistance to targeted therapies. Cancer Treat Rev 2020; 88:102043. [PMID: 32505806 DOI: 10.1016/j.ctrv.2020.102043] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 05/20/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023]
Abstract
Autophagy is a self-degradative cellular process, involved in stress response such as starvation, hypoxia, and oxidative stress. This mechanism balances macro-molecule recycling to regulate cell homeostasis. In cancer, autophagy play a role in the development and progression, while several studies describe it as one of the key processes in drug resistance. In the last years, in addition to standard anti-cancer treatments such as chemotherapies and irradiation, targeted therapy became one of the most adopted strategies in clinical practices, mainly due to high specificity and reduced side effects. However, similar to standard treatments, drug resistance is the main challenge in most patients. Here, we summarize recent studies that investigated the role of autophagy in drug resistance after targeted therapy in different types of cancers. We highlight positive results and limitations of pre-clinical and clinical studies in which autophagy inhibitors are used in combination with targeted therapies.
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Affiliation(s)
- Luigi Mele
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy
| | - Vitale Del Vecchio
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy
| | - Davide Liccardo
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy
| | - Claudia Prisco
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy; The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK
| | - Melanie Schwerdtfeger
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy; Department of Medicine IV -Division of Clinical Pharmacology-University of Munich, Germany
| | - Nirmal Robinson
- Centre for Cancer Biology, SA Pathology and University of South Australia, GPO Box 2471, Adelaide, Australia
| | - Vincenzo Desiderio
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy
| | - Virginia Tirino
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy
| | - Gianpaolo Papaccio
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy.
| | - Marcella La Noce
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy
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Kofron CP, Chapman A. Breast Cancer With Brain Metastases: Perspective From a Long-Term Survivor. Integr Cancer Ther 2020; 19:1534735419890017. [PMID: 31906724 PMCID: PMC6947880 DOI: 10.1177/1534735419890017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The purpose of this essay is to inform others that it is possible to survive breast cancer with brain metastases. The second author is the subject patient and a long-term survivor of systemic metastatic breast cancer with numerous brain metastases (corresponding to 8% survivor group). We credit her survival to a combination of (1) medicine as practiced by an excellent oncologist with whom we developed a partnership to manage the patient’s health, (2) our informed exploration of the available scientific knowledge including a review of scientific research articles that go beyond conventional care, and (3) the patient’s supplementation with numerous repurposed drugs and other substances reported to have antitumor properties. Alongside her conventional treatment (the medical standard of care), it seems likely that this supplementation has been a key factor in the patient’s long-term survival. We also point out that the lack of follow-up magnetic resonance imaging brain scans for early detection of brain metastases poses substantial risks for patients with HER2+ metastatic breast cancer in non–central nervous system locations. Thus, we suggest that research be conducted on such early detection for possible inclusion in the recommendations for the medical standard of care. Finally, medical doctors and also patients with backgrounds in biological science may wish to consider potential options and advantages of repurposed drugs and other substances reported in scientific publications when the medical standard of care has limited options for advanced cancer and other severe chronic health conditions. However, any efforts along this line by patients should be in collaboration with their medical doctors.
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Affiliation(s)
| | - Angela Chapman
- Biology Program, California State University Channel Islands, Camarillo, CA, USA
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35
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Singh S, Shukla R. Key Signaling Pathways Engaged in Cancer Management: Current Update. CURRENT CANCER THERAPY REVIEWS 2020. [DOI: 10.2174/1573394714666180904122412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
<P>Background: Till today cancer is still challenging to treat and needs more active therapeutic approaches. Participation of complex multi-pathway cell propagation instrument is a noteworthy issue in creating active anticancer therapeutic methodologies. Immune evasions, metabolic modifications, imperfect apoptotic component, modification in upstream or downstream RAS signaling, altered nuclear factor kappa B actions, imbalanced autophagy design and distortedly controlled angiogenesis are distinguishing features of cancer. </P><P> Methods: On the basis of systemic research and analysis of the current online available database, we analyzed and reported about the key signaling pathway engaged with cancer development outlining the effectiveness of different therapeutic measures and targets that have been created or are being researched to obstruct the cancer development. </P><P> Results: A number of signaling pathways, for example, resistant, metabolism, apoptosis, RAS protein, nuclear factor kappa B, autophagy, and angiogenesis have been perceived as targets for drug treatment to control the advancement, development and administration of cancer. </P><P> Conclusion: A noteworthy challenge for future medication advancement is to detail a synthesis treatment influencing distinctive targets to enhance the treatment of cancer.</P>
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Affiliation(s)
- Sanjiv Singh
- National Institute of Pharmaceutical Science and Education, Shree Bhawani Paper Mill Road, ITI Compound, Raebareli-229010 (U.P.), India
| | - Rahul Shukla
- National Institute of Pharmaceutical Science and Education, Shree Bhawani Paper Mill Road, ITI Compound, Raebareli-229010 (U.P.), India
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Zheng X, Jin X, Liu X, Liu B, Li P, Ye F, Zhao T, Chen W, Li Q. Inhibition of endoplasmic reticulum stress-induced autophagy promotes the killing effect of X-rays on sarcoma in mice. Biochem Biophys Res Commun 2019; 522:612-617. [PMID: 31785812 DOI: 10.1016/j.bbrc.2019.11.160] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 11/22/2019] [Indexed: 12/30/2022]
Abstract
Endoplasmic reticulum (ER) stress is a conserved cellular process for cells to clear unfolded or misfolded proteins and maintain cell homeostasis under stress conditions. Autophagy may act as a pro-survival strategy to cope with multiple stress conditions in tumor progression and distant metastasis. Although many studies have demonstrated that there is a close correlation between radiation-induced ER stress and autophagy, the molecular mechanisms currently remain unclear. In the present study, we performed an in vivo study concerning the effect of autophagy induced by ER stress on the radiosensitivity of mouse sarcoma using X-rays. Our results documented that X-rays could induce ER stress in sarcoma and then autophagy was activated by unfolded protein response (UPR) through the IRE1-JNK-pBcl2-Beclin1 signaling axis. The induction of autophagy caused a decline in cell apoptosis while inhibiting the autophagy resulted in increased apoptosis and inhibition of tumor progression. Combined treatment of X-ray exposure and chloroquine increased ER stress-related apoptosis and enhanced the radiosensitivity of mouse sarcoma that was not sensitive to X-ray irradiation alone. Thus, our study indicates that inhibition of ER stress-induced autophagy might be a novel strategy to improve the efficacy of radiotherapy against radioresistant sarcoma.
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Affiliation(s)
- Xiaogang Zheng
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou, 730000, China
| | - Xiaodong Jin
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou, 730000, China
| | - Xiongxiong Liu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou, 730000, China
| | - Bingtao Liu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou, 730000, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ping Li
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou, 730000, China
| | - Fei Ye
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou, 730000, China
| | - Ting Zhao
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou, 730000, China
| | - Weiqiang Chen
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou, 730000, China
| | - Qiang Li
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, 730000, China; Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou, 730000, China.
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Arnaout A, Robertson SJ, Pond GR, Lee H, Jeong A, Ianni L, Kroeger L, Hilton J, Coupland S, Gottlieb C, Hurley B, McCarthy A, Clemons M. A randomized, double-blind, window of opportunity trial evaluating the effects of chloroquine in breast cancer patients. Breast Cancer Res Treat 2019; 178:327-335. [PMID: 31392517 DOI: 10.1007/s10549-019-05381-y] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 07/27/2019] [Indexed: 12/17/2022]
Abstract
PURPOSE Chloroquine has demonstrated anti-tumor activities through autophagy inhibition and cell cycle disruption. This study aimed to assess the effect of single-agent chloroquine on breast tumor cellular proliferation in a randomized, phase II, double-blind, placebo-controlled, pre-surgical window of opportunity trial. METHODS Patients with newly diagnosed breast cancer were randomized 2:1 to chloroquine 500 mg daily or placebo for 2- to 6-weeks prior to their breast surgery. The primary outcome was the relative change in measures of proliferation (Ki67) in primary breast cancer cells pre- and post-treatment. Adverse events and toxicity profiles were also evaluated. RESULTS From September 2015 to December 2016, 70 patients were randomized [46 (66%) chloroquine and 24 (34%) placebo]. Ten patients who were randomized to chloroquine withdrew from study due to adverse events. Mean duration of drug intake was 15 days (range 14-29 days). There were no significant differences between the chloroquine or placebo arms with respect to either the percentage change (- 0.4 vs. - 1.2, p = 0.088) or absolute change (- 2.0% vs. - 5.2%, p = 0.066) in Ki67 index pre- and post-drug treatment. Although adverse effects were minimal and all classified as grade 1, the effects were significant enough to cause nearly 15% of patients to discontinue therapy. CONCLUSIONS Treatment with single-agent chloroquine 500 mg daily in the preoperative setting was not associated with any significant effects on breast cancer cellular proliferation. It was, however, associated with toxicity that may affect its broader use in oncology.
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Affiliation(s)
- Angel Arnaout
- Division of Surgical Oncology, Department of Surgery, Ottawa Hospital, Ottawa, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada
| | | | - Gregory R Pond
- Department of Oncology, McMaster University, Hamilton, Canada
| | - Hoyun Lee
- Health Sciences North Research Institute, Sudbury, Canada
- Department of Medicine, University of Ottawa, Ottawa, Canada
| | - Ahwon Jeong
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Luisa Ianni
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada
- Ottawa Hospital Breast Health Centre, Ottawa, Canada
| | - Lynne Kroeger
- Ottawa Hospital Breast Health Centre, Ottawa, Canada
| | - John Hilton
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada
- Division of Medical Oncology, Department of Medicine, University of Ottawa and Ottawa Hospital Cancer Center, The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, Canada
| | - Stuart Coupland
- Department of Ophthalmology, University of Ottawa, Ottawa, Canada
| | - Chloe Gottlieb
- Department of Ophthalmology, University of Ottawa, Ottawa, Canada
| | - Bernard Hurley
- Department of Ophthalmology, University of Ottawa, Ottawa, Canada
| | - Anne McCarthy
- Division of Infectious Diseases, Department of Medicine, Ottawa Hospital, Ottawa, Canada
| | - Mark Clemons
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada.
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.
- Division of Medical Oncology, Department of Medicine, University of Ottawa and Ottawa Hospital Cancer Center, The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, Canada.
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Pérez-Hernández M, Arias A, Martínez-García D, Pérez-Tomás R, Quesada R, Soto-Cerrato V. Targeting Autophagy for Cancer Treatment and Tumor Chemosensitization. Cancers (Basel) 2019; 11:E1599. [PMID: 31635099 PMCID: PMC6826429 DOI: 10.3390/cancers11101599] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/14/2019] [Accepted: 10/16/2019] [Indexed: 12/15/2022] Open
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.
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Affiliation(s)
- Marta Pérez-Hernández
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, 08905 Barcelona, Spain.
- Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
| | - Alain Arias
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, 08905 Barcelona, Spain.
- Department of Integral Adult Dentistry, Research Centre for Dental Sciences (CICO), Universidad de La Frontera, Temuco 4811230, Chile.
- Research Group of Health Sciences, Faculty of Health Sciences, Universidad Adventista de Chile, Chillán 3780000, Chile.
| | - David Martínez-García
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, 08905 Barcelona, Spain.
- Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
| | - Ricardo Pérez-Tomás
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, 08905 Barcelona, Spain.
- Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
| | - Roberto Quesada
- Department of Chemistry, Universidad de Burgos, 09001 Burgos, Spain.
| | - Vanessa Soto-Cerrato
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Universitat de Barcelona, 08905 Barcelona, Spain.
- Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
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Guerra F, Bucci C. Role of the RAB7 Protein in Tumor Progression and Cisplatin Chemoresistance. Cancers (Basel) 2019; 11:cancers11081096. [PMID: 31374919 PMCID: PMC6721790 DOI: 10.3390/cancers11081096] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 07/23/2019] [Accepted: 07/30/2019] [Indexed: 12/19/2022] Open
Abstract
RAB7 is a small guanosine triphosphatase (GTPase) extensively studied as regulator of vesicular trafficking. Indeed, its role is fundamental in several steps of the late endocytic pathway, including endosome maturation, transport from early endosomes to late endosomes and lysosomes, clustering and fusion of late endosomes and lysosomes in the perinuclear region and lysosomal biogenesis. Besides endocytosis, RAB7 is important for a number of other cellular processes among which, autophagy, apoptosis, signaling, and cell migration. Given the importance of RAB7 in these cellular processes, the interest to study the role of RAB7 in cancer progression is widely grown. Here, we describe the current understanding of oncogenic and oncosuppressor functions of RAB7 analyzing cellular context and other environmental factors in which it elicits pro and/or antitumorigenic effects. We also discuss the role of RAB7 in cisplatin resistance associated with its ability to regulate the late endosomal pathway, lysosomal biogenesis and extracellular vesicle secretion. Finally, we examined the potential cancer therapeutic strategies targeting the different molecular events in which RAB7 is involved.
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Affiliation(s)
- Flora Guerra
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni 165, 73100 Lecce, Italy.
| | - Cecilia Bucci
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni 165, 73100 Lecce, Italy.
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HSP90 inhibitor DPB induces autophagy and more effectively apoptosis in A549 cells combined with autophagy inhibitors. In Vitro Cell Dev Biol Anim 2019; 55:349-354. [PMID: 30989449 DOI: 10.1007/s11626-019-00327-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Accepted: 01/25/2019] [Indexed: 01/10/2023]
Abstract
In our previous study, we proved that a novel Heat shock protein 90 (HSP90) inhibitor 4-(3-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) benzoic acid (DPB) could inhibit A549 lung cancer cell growth via inducing apoptosis. However, whether DPB affects autophagy is still unknown. Here, we investigated the effects of DPB on autophagy and the improved anti-cancer activity in A549 lung cancer cells. Aggregation of LC3-II was observed using laser scanning confocal microscopy in GFP-LC3 stably transfected U87 cells. Autophagy and apoptosis-related protein levels were examined by Western blot analysis. It is suggested that treatment with DPB (5-20 μmol/L) induced mTOR-independent autophagy in dose- and time-dependent manners. Pre-treatment A549 cells with autophagy inhibitor 3-methyladenine (3-MA, 5 mmol/L) enhanced DPB-induced apoptosis. And, DPB inhibited A549 cell growth more effectively in combination with autophagy inhibitors 3-MA (5 mmol/L) or 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO, 30 μmol/L). These results illustrated that as a potential and promising HSP90 inhibitor, DPB could be utilized in the treatment of cancer combined with the autophagy inhibitor.
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Sharma G, Guardia CM, Roy A, Vassilev A, Saric A, Griner LN, Marugan J, Ferrer M, Bonifacino JS, DePamphilis ML. A family of PIKFYVE inhibitors with therapeutic potential against autophagy-dependent cancer cells disrupt multiple events in lysosome homeostasis. Autophagy 2019; 15:1694-1718. [PMID: 30806145 DOI: 10.1080/15548627.2019.1586257] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
High-throughput screening identified 5 chemical analogs (termed the WX8-family) that disrupted 3 events in lysosome homeostasis: (1) lysosome fission via tubulation without preventing homotypic lysosome fusion; (2) trafficking of molecules into lysosomes without altering lysosomal acidity, and (3) heterotypic fusion between lysosomes and autophagosomes. Remarkably, these compounds did not prevent homotypic fusion between lysosomes, despite the fact that homotypic fusion required some of the same machinery essential for heterotypic fusion. These effects varied 400-fold among WX8-family members, were time and concentration dependent, reversible, and resulted primarily from their ability to bind specifically to the PIKFYVE phosphoinositide kinase. The ability of the WX8-family to prevent lysosomes from participating in macroautophagy/autophagy suggested they have therapeutic potential in treating autophagy-dependent diseases. In fact, the most potent family member (WX8) was 100-times more lethal to 'autophagy-addicted' melanoma A375 cells than the lysosomal inhibitors hydroxychloroquine and chloroquine. In contrast, cells that were insensitive to hydroxychloroquine and chloroquine were also insensitive to WX8. Therefore, the WX8-family of PIKFYVE inhibitors provides a basis for developing drugs that could selectively kill autophagy-dependent cancer cells, as well as increasing the effectiveness of established anti-cancer therapies through combinatorial treatments. Abbreviations: ACTB: actin beta; Baf: bafilomycin A1; BECN1: beclin 1; BODIPY: boron-dipyrromethene; BORC: BLOC-1 related complex; BRAF: B-Raf proto-oncogene, serine/threonine kinase; BSA: bovine serum albumin; CTSD: cathepsin D; CQ: chloroquine; DNA: deoxyribonucleic acid; EC50: half maximal effective concentration; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HCQ: hydroxychloroquine; HOPS complex: homotypic fusion and protein sorting complex; Kd: equilibrium binding constant; IC50: half maximal inhibitory concentration; KO: knockout; LAMP1: lysosomal associated membrane protein 1; MAP1LC3A: microtubule associated protein 1 light chain 3 alpha; MES: 2-(N-morpholino)ethanesulphonic acid; MTOR: mechanistic target of rapamycin kinase; μM: micromolar; NDF: 3-methylbenzaldehyde (2,6-dimorpholin-4-ylpyrimidin-4-yl)hydrazine;NEM: N-ethylmaleimide; NSF: N-ethylmaleimide sensitive factor; PBS: phosphate-buffered saline; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; PIP4K2C: phosphatidylinositol-5-phosphate 4-kinase type 2 gamma; PtdIns3P: phosphatidylinositol 3-phosphate; PtdIns(3,5)P2: phosphatidylinositol 3,5-biphosphate; RFP: red fluorescent protein; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase B1; SQSTM1: sequestosome 1; TWEEN 20: polysorbate 20; V-ATPase: vacuolar-type H+-translocating ATPase; VPS39: VPS39 subunit of HOPS complex; VPS41: VPS41 subunit of HOPS complex; WWL: benzaldehyde [2,6-di(4-morpholinyl)-4-pyrimidinyl]hydrazone; WX8: 1H-indole-3-carbaldehyde [4-anilino-6-(4-morpholinyl)-1,3,5-triazin-2-yl]hydrazine; XBA: N-(3-chloro-4-fluorophenyl)-4,6-dimorpholino-1,3,5-triazin-2-amine hydrochloride; XB6: N-(4-ethylphenyl)-4,6-dimorpholino-1,3,5-triazin-2-amine hydrochloride.
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Affiliation(s)
- Gaurav Sharma
- Division of Developmental Biology, National Institute of Child Health & Human Development, National Institutes of Health , Bethesda , MD , USA
| | - Carlos M Guardia
- Cell Biology and Neurobiology Branch, National Institute of Child Health & Human Development, National Institutes of Health , Bethesda , MD , USA
| | - Ajit Roy
- Division of Developmental Biology, National Institute of Child Health & Human Development, National Institutes of Health , Bethesda , MD , USA
| | - Alex Vassilev
- Division of Developmental Biology, National Institute of Child Health & Human Development, National Institutes of Health , Bethesda , MD , USA
| | - Amra Saric
- Cell Biology and Neurobiology Branch, National Institute of Child Health & Human Development, National Institutes of Health , Bethesda , MD , USA
| | - Lori N Griner
- Division of Developmental Biology, National Institute of Child Health & Human Development, National Institutes of Health , Bethesda , MD , USA
| | - Juan Marugan
- Division of Pre-Clinical Innovation, NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health , Rockville , MD , USA
| | - Marc Ferrer
- Division of Pre-Clinical Innovation, NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health , Rockville , MD , USA
| | - Juan S Bonifacino
- Cell Biology and Neurobiology Branch, National Institute of Child Health & Human Development, National Institutes of Health , Bethesda , MD , USA
| | - Melvin L DePamphilis
- Division of Developmental Biology, National Institute of Child Health & Human Development, National Institutes of Health , Bethesda , MD , USA
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Takeda M, Koseki J, Takahashi H, Miyoshi N, Nishida N, Nishimura J, Hata T, Matsuda C, Mizushima T, Yamamoto H, Ishii H, Doki Y, Mori M, Haraguchi N. Disruption of Endolysosomal RAB5/7 Efficiently Eliminates Colorectal Cancer Stem Cells. Cancer Res 2019; 79:1426-1437. [PMID: 30765602 DOI: 10.1158/0008-5472.can-18-2192] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 11/13/2018] [Accepted: 02/11/2019] [Indexed: 02/04/2023]
Abstract
Given that cancer stem cells (CSC) play a key role in drug resistance and relapse, targeting CSCs remains promising in cancer therapy. Here we show that RAB5/7, which are involved in the endolysosomal pathway, play key roles in the maintenance of CSC survival via regulation of the mitophagic pathway. Inhibition of RAB5/7 efficiently eliminated colorectal CSCs and disrupted cancer foci. In addition, we identified mefloquine hydrochloride, an antimalarial drug, as a novel RAB5/7 inhibitor and promising colorectal CSC-targeting drug. Endolysosomal RAB5/7 and LAMP1/2 mediated parkin-dependent mitochondrial clearance and modulated mitophagy through lysosomal dynamics. In a patient-derived xenograft (PDX) model of colon cancer, treatment with mefloquine resulted in suppression of mitophagic PINK1/PARKIN and increased mitochondrial disorder and mitochondria-induced apoptosis without apparent side effects. These results suggest that the combination of mefloquine with chemotherapeutic agents in the PDX model potentially disrupts the hierarchy of colorectal cancer cells and identify endolysosomal RAB5/7 and LAMP1/2 as promising therapeutic targets in CSCs. SIGNIFICANCE: These findings show that endosomal/lysosomal RAB5 and RAB7, which regulate mitophagy, are essential for the survival of colon cancer stem cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1426/F1.large.jpg.
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Affiliation(s)
- Mitsunobu Takeda
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Jun Koseki
- Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Norikatsu Miyoshi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Naohiro Nishida
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Junichi Nishimura
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Taishi Hata
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Chu Matsuda
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hirofumi Yamamoto
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hideshi Ishii
- Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Naotsugu Haraguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
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Lin X, Peng Z, Wang X, Zou J, Chen D, Chen Z, Li Z, Dong B, Gao J, Shen L. Targeting autophagy potentiates antitumor activity of Met-TKIs against Met-amplified gastric cancer. Cell Death Dis 2019; 10:139. [PMID: 30760701 PMCID: PMC6374362 DOI: 10.1038/s41419-019-1314-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 12/05/2018] [Accepted: 12/20/2018] [Indexed: 12/19/2022]
Abstract
Met tyrosine kinase inhibitors (Met-TKIs) subjected to ongoing clinical trials are a promising option for Met-amplified gastric cancer (GC), but how to optimize their antitumor activity especially with combination schemes remains unclear. Since autophagy is known to be initiated by Met-TKIs, we investigated its underlying mechanisms and therapeutic potentials of Met-TKIs combined with autophagy inhibitors against Met-amplified GC. As expected, four Met-TKIs induced autophagy in Met-amplified GC cells marked by p62 degradation, LC3-II accumulation and increased LC3-positive puncta. Autophagy flux activation by Met-TKIs was further validated with combined lysosomal inhibitors, bafilomycin A1 (Baf A1) and hydroxychloroquine (HCQ). Molecular investigations reveal that autophagy induction along with mTOR and ULK1 de-phosphorylation upon Met-TKI treatment could be relieved by hepatocyte growth factor (HGF) and mTOR agonist MHY1485 (MHY), suggesting that autophagy was initiated by Met-TKIs via Met/mTOR/ULK1 cascade. Intriguingly, Met-TKIs further suppressed cell survival and tumor growth in the presence of autophagy blockade in Met-amplified GC preclinical models. Thus, these findings indicate Met/mTOR/ULK1 cascade responsible for Met-TKI-mediated autophagy and Met-TKIs combined with autophagy inhibitors as a promising choice to treat Met-amplified GC.
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Affiliation(s)
- Xiaoting Lin
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Xiaojuan Wang
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jianling Zou
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Dongshao Chen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zuhua Chen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zhongwu Li
- Department of Pathology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Bin Dong
- Department of Pathology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jing Gao
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Lin Shen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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Autophagy and Its Role in Protein Secretion: Implications for Cancer Therapy. Mediators Inflamm 2018; 2018:4231591. [PMID: 30622432 PMCID: PMC6304875 DOI: 10.1155/2018/4231591] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/26/2018] [Accepted: 10/02/2018] [Indexed: 12/11/2022] Open
Abstract
Autophagy is a protein and organelle degradation pathway important for the maintenance of cytoplasmic homeostasis and for providing nutrients for survival in response to stress conditions. Recently, autophagy has been shown to be important for the secretion of diverse proteins involved in inflammation, intercellular signaling, and cancer progression. The role of autophagy in cancer depends on the stage of tumorigenesis, serving a tumor-suppressor role before transformation and a tumor-survival function once a tumor is established. We review recent evidence demonstrating the complexity of autophagy regulation during cancer, considering the interaction of autophagy with protein secretion pathways. Autophagy manipulation during cancer treatment is likely to affect protein secretion andinter-cellular signaling either to the neighboring cancer cells or to the antitumoral immune response. This will be an important consideration during cancer therapy since several clinical trials are trying to manipulate autophagy in combination with chemotherapy for the treatment of diverse types of cancers.
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Aga T, Endo K, Tsuji A, Aga M, Moriyama-Kita M, Ueno T, Nakanishi Y, Hatano M, Kondo S, Sugimoto H, Wakisaka N, Yoshizaki T. Inhibition of autophagy by chloroquine makes chemotherapy in nasopharyngeal carcinoma more efficient. Auris Nasus Larynx 2018; 46:443-450. [PMID: 30514592 DOI: 10.1016/j.anl.2018.10.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 09/18/2018] [Accepted: 10/10/2018] [Indexed: 01/11/2023]
Abstract
OBJECTIVES A combination of platinum-based chemotherapy and radiotherapy is the standard treatment for nasopharyngeal carcinoma (NPC). However, the efficacy of chemotherapy has reached a plateau. Many autophagy studies suggest that autophagy can either promote or suppress to cancer progression. Thus, a role of autophagy in the acquisition of chemoradioresistance has recently been a notable event. Therefore, we examined the relationship between autophagy and chemotherapy in NPC. METHODS The expression of Beclin 1 and microtubule-associated protein light chain 3 (LC3), a marker of autophagy, was determined by immunohistochemistry in the biopsy samples of patients with NPC before and after the first course of chemotherapy. Additionally, to investigate in the effect of autophagy suppression in chemotherapy, NPC cell line C666-1 cells were treated with cisplatin and/or chloroquine, an inhibitor of autophagy. RESULTS The expression of Beclin 1 increased after chemotherapy in all patients. In NPC cell line C666-1, compared to cisplatin alone, combination therapy (cisplatin and chloroquine) reduced cell viability, and promoted cell apoptosis. CONCLUSIONS These results suggest that autophagy, represented by Beclin 1, is upregulated after chemotherapy in both in vitro and in vivo NPC studies. Inhibition of autophagy could therefore be new strategy for NPC treatment.
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Affiliation(s)
- Tomomi Aga
- Division of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Kazuhira Endo
- Division of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Akira Tsuji
- Division of Otolaryngology, Toyama City Hospital, Toyama, Japan
| | - Mitsuharu Aga
- Division of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Makiko Moriyama-Kita
- Division of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Takayoshi Ueno
- Division of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Yosuke Nakanishi
- Division of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Miyako Hatano
- Division of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Satoru Kondo
- Division of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Hisashi Sugimoto
- Division of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Naohiro Wakisaka
- Division of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Tomokazu Yoshizaki
- Division of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.
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Li Y, Cao F, Li M, Li P, Yu Y, Xiang L, Xu T, Lei J, Tai YY, Zhu J, Yang B, Jiang Y, Zhang X, Duo L, Chen P, Yu X. Hydroxychloroquine induced lung cancer suppression by enhancing chemo-sensitization and promoting the transition of M2-TAMs to M1-like macrophages. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:259. [PMID: 30373678 PMCID: PMC6206903 DOI: 10.1186/s13046-018-0938-5] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 10/18/2018] [Indexed: 01/17/2023]
Abstract
BACKGROUND Lysosome-associated agents have been implicated as possible chemo-sensitizers and immune regulators for cancer chemotherapy. We investigated the potential roles and mechanisms of hydroxychloroquine (HCQ) in combination with chemotherapy in lung cancer treatment. METHODS The effects of combined treatment on non-small cell lung cancer (NSCLC) were investigated using cell viability assays and animal models. The influence of HCQ on lysosomal pH was evaluated by lysosomal sensors and confocal microscopy. The effects of HCQ on the tumour immune microenvironment were analysed by flow cytometry. RESULTS HCQ elevates the lysosomal pH of cancer cells to inactivate P-gp while increasing drug release from the lysosome into the nucleus. Furthermore, single HCQ therapy inhibits lung cancer by inducing macrophage-modulated anti-tumour CD8+ T cell immunity. Moreover, HCQ could promote the transition of M2 tumour-associated macrophages (TAMs) into M1-like macrophages, leading to CD8+ T cell infiltration into the tumour microenvironment. CONCLUSIONS HCQ exerts anti-NSCLC cells effects by reversing the drug sequestration in lysosomes and enhancing the CD8+ T cell immune response. These findings suggest that HCQ could act as a promising chemo-sensitizer and immune regulator for lung cancer chemotherapy in the clinic.
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Affiliation(s)
- Yong Li
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang middle Rd, Shiyan, 442000, Hubei, China
| | - Fengjun Cao
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang middle Rd, Shiyan, 442000, Hubei, China
| | - Mingxing Li
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Pindong Li
- Cancer Center of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yuandong Yu
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang middle Rd, Shiyan, 442000, Hubei, China.,Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Longchao Xiang
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang middle Rd, Shiyan, 442000, Hubei, China
| | - Tao Xu
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang middle Rd, Shiyan, 442000, Hubei, China
| | - Jinhua Lei
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang middle Rd, Shiyan, 442000, Hubei, China
| | - Yun Yan Tai
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang middle Rd, Shiyan, 442000, Hubei, China
| | - Jianyong Zhu
- Department of Respiratory Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Bingbing Yang
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang middle Rd, Shiyan, 442000, Hubei, China.,Teaching practice base of Oncology, Shiyan Renmin Hospital, Jinzhou Medical University, Shiyan, 442000, China
| | - Yingpin Jiang
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang middle Rd, Shiyan, 442000, Hubei, China
| | - Xiufang Zhang
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang middle Rd, Shiyan, 442000, Hubei, China.,Teaching practice base of Oncology, Shiyan Renmin Hospital, Jinzhou Medical University, Shiyan, 442000, China
| | - Long Duo
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang middle Rd, Shiyan, 442000, Hubei, China
| | - Ping Chen
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang middle Rd, Shiyan, 442000, Hubei, China
| | - Xiongjie Yu
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang middle Rd, Shiyan, 442000, Hubei, China. .,Institute of Cancer Research, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, China.
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47
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Sannino S, Guerriero CJ, Sabnis AJ, Stolz DB, Wallace CT, Wipf P, Watkins SC, Bivona TG, Brodsky JL. Compensatory increases of select proteostasis networks after Hsp70 inhibition in cancer cells. J Cell Sci 2018; 131:jcs217760. [PMID: 30131440 PMCID: PMC6140321 DOI: 10.1242/jcs.217760] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 08/02/2018] [Indexed: 12/13/2022] Open
Abstract
Cancer cells thrive when challenged with proteotoxic stress by inducing components of the protein folding, proteasome, autophagy and unfolded protein response (UPR) pathways. Consequently, specific molecular chaperones have been validated as targets for anti-cancer therapies. For example, inhibition of Hsp70 family proteins (hereafter Hsp70) in rhabdomyosarcoma triggers UPR induction and apoptosis. To define how these cancer cells respond to compromised proteostasis, we compared rhabdomyosarcoma cells that were sensitive (RMS13) or resistant (RMS13-R) to the Hsp70 inhibitor MAL3-101. We discovered that endoplasmic reticulum-associated degradation (ERAD) and autophagy were activated in RMS13-R cells, suggesting that resistant cells overcome Hsp70 ablation by increasing misfolded protein degradation. Indeed, RMS13-R cells degraded ERAD substrates more rapidly than RMS cells and induced the autophagy pathway. Surprisingly, inhibition of the proteasome or ERAD had no effect on RMS13-R cell survival, but silencing of select autophagy components or treatment with autophagy inhibitors restored MAL3-101 sensitivity and led to apoptosis. These data indicate a route through which cancer cells overcome a chaperone-based therapy, define how cells can adapt to Hsp70 inhibition, and demonstrate the value of combined chaperone and autophagy-based therapies.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Sara Sannino
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | | | - Amit J Sabnis
- Department of Pediatrics, University of California, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA
| | - Donna Beer Stolz
- Department of Medicine, University of California, San Francisco, CA 94143, USA
| | - Callen T Wallace
- Department of Medicine, University of California, San Francisco, CA 94143, USA
| | - Peter Wipf
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Simon C Watkins
- Department of Medicine, University of California, San Francisco, CA 94143, USA
| | - Trever G Bivona
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Jeffrey L Brodsky
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA
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48
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Mauthe M, Orhon I, Rocchi C, Zhou X, Luhr M, Hijlkema KJ, Coppes RP, Engedal N, Mari M, Reggiori F. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy 2018; 14:1435-1455. [PMID: 29940786 PMCID: PMC6103682 DOI: 10.1080/15548627.2018.1474314] [Citation(s) in RCA: 1413] [Impact Index Per Article: 201.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 05/01/2018] [Accepted: 05/02/2018] [Indexed: 02/08/2023] Open
Abstract
Macroautophagy/autophagy is a conserved transport pathway where targeted structures are sequestered by phagophores, which mature into autophagosomes, and then delivered into lysosomes for degradation. Autophagy is involved in the pathophysiology of numerous diseases and its modulation is beneficial for the outcome of numerous specific diseases. Several lysosomal inhibitors such as bafilomycin A1 (BafA1), protease inhibitors and chloroquine (CQ), have been used interchangeably to block autophagy in in vitro experiments assuming that they all primarily block lysosomal degradation. Among them, only CQ and its derivate hydroxychloroquine (HCQ) are FDA-approved drugs and are thus currently the principal compounds used in clinical trials aimed to treat tumors through autophagy inhibition. However, the precise mechanism of how CQ blocks autophagy remains to be firmly demonstrated. In this study, we focus on how CQ inhibits autophagy and directly compare its effects to those of BafA1. We show that CQ mainly inhibits autophagy by impairing autophagosome fusion with lysosomes rather than by affecting the acidity and/or degradative activity of this organelle. Furthermore, CQ induces an autophagy-independent severe disorganization of the Golgi and endo-lysosomal systems, which might contribute to the fusion impairment. Strikingly, HCQ-treated mice also show a Golgi disorganization in kidney and intestinal tissues. Altogether, our data reveal that CQ and HCQ are not bona fide surrogates for other types of late stage lysosomal inhibitors for in vivo experiments. Moreover, the multiple cellular alterations caused by CQ and HCQ call for caution when interpreting results obtained by blocking autophagy with this drug.
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Affiliation(s)
- Mario Mauthe
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Cell Biology, University Medical Center Utrecht, Center for Molecular Medicine, Utrecht, The Netherlands
| | - Idil Orhon
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Cecilia Rocchi
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Xingdong Zhou
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, People’s Republic of China
| | - Morten Luhr
- Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership for Molecular Medicine, University of Oslo, Oslo, Norway
| | - Kerst-Jan Hijlkema
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert P. Coppes
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Nikolai Engedal
- Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership for Molecular Medicine, University of Oslo, Oslo, Norway
| | - Muriel Mari
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Cell Biology, University Medical Center Utrecht, Center for Molecular Medicine, Utrecht, The Netherlands
| | - Fulvio Reggiori
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Cell Biology, University Medical Center Utrecht, Center for Molecular Medicine, Utrecht, The Netherlands
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49
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Fu Z, Cheng X, Kuang J, Feng H, Chen L, Liang J, Shen X, Yuen S, Peng C, Shen B, Jin Z, Qiu W. CQ sensitizes human pancreatic cancer cells to gemcitabine through the lysosomal apoptotic pathway via reactive oxygen species. Mol Oncol 2018; 12:529-544. [PMID: 29453806 PMCID: PMC5891043 DOI: 10.1002/1878-0261.12179] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 01/23/2018] [Accepted: 01/24/2018] [Indexed: 12/13/2022] Open
Abstract
As an established anticancer drug, gemcitabine (GEM) is an effective systemic treatment for advanced pancreatic cancer (PC). However, little is known about the potential effectors that may modify tumour cell sensitivity towards GEM. Autophagy, as a physiological cellular mechanism, is involved in both cell survival and cell death. In this study, we found that exposure to GEM induced a significant increase in autophagy in a dose-dependent manner in PANC-1 and BxPC-3 cells. Inhibition of autophagy by chloroquine (CQ) and ATG7 siRNA increased GEM-induced cytotoxicity, and CQ was more effective than ATG7 siRNA. Moreover, CQ significantly enhanced GEM-induced apoptosis, while ATG7 siRNA failed to show the similar effect. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that GEM with CQ pretreatment markedly triggered reactive oxygen species (ROS) boost and then increased lysosomal membrane permeability. Consequently, cathepsins released from lysosome into the cytoplasm induced apoptosis. We showed that CQ could enhance PC cells response to GEM in xenograft models. In conclusion, our data showed that CQ sensitized PC cells to GEM through the lysosomal apoptotic pathway via ROS. Thus, CQ as a potential adjuvant to GEM might represent an attractive therapeutic strategy for PC treatment.
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Affiliation(s)
- Zhiping Fu
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xi Cheng
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jie Kuang
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Haoran Feng
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Lingxie Chen
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Juyong Liang
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xiaonan Shen
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Stanley Yuen
- Biology Chemistry MajorUniversity At AlbanyNew YorkNYUSA
| | - Chenghong Peng
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Baiyong Shen
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Zhijian Jin
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Weihua Qiu
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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50
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Identification of breast cancer cell subtypes sensitive to ATG4B inhibition. Oncotarget 2018; 7:66970-66988. [PMID: 27556700 PMCID: PMC5341851 DOI: 10.18632/oncotarget.11408] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Accepted: 08/09/2016] [Indexed: 01/22/2023] Open
Abstract
Autophagy, a lysosome-mediated degradation and recycling process, functions in advanced malignancies to promote cancer cell survival and contribute to cancer progression and drug resistance. While various autophagy inhibition strategies are under investigation for cancer treatment, corresponding patient selection criteria for these autophagy inhibitors need to be developed. Due to its central roles in the autophagy process, the cysteine protease ATG4B is one of the autophagy proteins being pursued as a potential therapeutic target. In this study, we investigated the expression of ATG4B in breast cancer, a heterogeneous disease comprised of several molecular subtypes. We examined a panel of breast cancer cell lines, xenograft tumors, and breast cancer patient specimens for the protein expression of ATG4B, and found a positive association between HER2 and ATG4B protein expression. We showed that HER2-positive cells, but not HER2-negative breast cancer cells, require ATG4B to survive under stress. In HER2-positive cells, cytoprotective autophagy was dependent on ATG4B under both starvation and HER2 inhibition conditions. Combined knockdown of ATG4B and HER2 by siRNA resulted in a significant decrease in cell viability, and the combination of ATG4B knockdown with trastuzumab resulted in a greater reduction in cell viability compared to trastuzumab treatment alone, in both trastuzumab-sensitive and -resistant HER2 overexpressing breast cancer cells. Together these results demonstrate a novel association of ATG4B positive expression with HER2 positive breast cancers and indicate that this subtype is suitable for emerging ATG4B inhibition strategies.
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