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Ivanova T, Sbirkov Y, Kazakova M, Sarafian V. Lysosomes and LAMPs as Autophagy Drivers of Drug Resistance in Colorectal Cancer. Cells 2025; 14:574. [PMID: 40277899 PMCID: PMC12025563 DOI: 10.3390/cells14080574] [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: 02/16/2025] [Revised: 04/04/2025] [Accepted: 04/08/2025] [Indexed: 04/26/2025] Open
Abstract
Colorectal cancer (CRC) is among the most malignant pathologies worldwide. A major factor contributing to the poor prognosis of neoplastic diseases is the development of drug resistance. It significantly reduces the utility of most therapeutic protocols and necessitates the search for novel biomarkers and treatment strategies to combat cancer. An evolutionarily conserved catabolic mechanism, autophagy maintains nutrient recycling and metabolic adaptation and is also closely related to carcinogenesis, playing a dual role. Autophagy inhibition can limit the growth of tumors and improve the response to cancer therapeutics. Lysosomes, key players in autophagy, are also considered promising targets for anticancer treatment. There are still insufficient data on the role of poorly studied glycoproteins related to autophagy, such as the lysosome-associated membrane glycoproteins (LAMPs). They can act as multifunctional molecules involved in a multitude of processes like autophagy and cancer development. In the current review, we summarize the recent data on the double-faceted role of autophagy in cancer with a focus on drug resistance in CRC and on the roles of lysosomes and LAMPs in these interconnected processes. Several lysosomotropic drugs are discussed as options to overcome cancer cell chemoresistance. The complex networks that underline defined autophagic pathways in the context of CRC carcinogenesis and the role of autophagy, especially of LAMPs as drivers of drug resistance, are outlined.
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Affiliation(s)
- Tsvetomira Ivanova
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria; (Y.S.); (M.K.)
- Research Division of Molecular and Regenerative Medicine, Research Institute at Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Yordan Sbirkov
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria; (Y.S.); (M.K.)
- Research Division of Molecular and Regenerative Medicine, Research Institute at Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Maria Kazakova
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria; (Y.S.); (M.K.)
- Research Division of Molecular and Regenerative Medicine, Research Institute at Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Victoria Sarafian
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria; (Y.S.); (M.K.)
- Research Division of Molecular and Regenerative Medicine, Research Institute at Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
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2
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Yanova M, Stepanova E, Maltseva D, Tonevitsky A. CD44 variant exons induce chemoresistance by modulating cell death pathways. Front Cell Dev Biol 2025; 13:1508577. [PMID: 40114966 PMCID: PMC11924683 DOI: 10.3389/fcell.2025.1508577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 02/03/2025] [Indexed: 03/22/2025] Open
Abstract
Cancer chemoresistance presents a challenge in oncology, often leading to treatment failure and disease progression. CD44, a multifunctional cell surface glycoprotein, has garnered attention for its involvement in various aspects of cancer biology. Through alternative splicing, CD44 can form isoforms with the inclusion of only standard exons, typical for normal tissue, or with the addition of variant exons, frequently expressed in cancer tissue and associated with chemoresistance. The functions of CD44 involved in regulation of cancer signaling pathways are being actively studied, and the significance of specific variant exons in modulating cell death pathways, central to the response of cancer cells to chemotherapy, begins to become apparent. This review provides a comprehensive analysis of the association of CD44 variant exons/total CD44 with clinical outcomes of patients undergoing chemotherapy. The role of CD44 variant exons v6, v9 and others with a significant effect on patient chemotherapy outcomes by means of key cellular death pathways such as apoptosis, ferroptosis and autophagy modulation is further identified, and their impact on drug resistance is highlighted. An overview of clinical trials aimed at targeting variant exon-containing isoforms is provided, and possible directions for further development of CD44-targeted therapeutic strategies are discussed.
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Affiliation(s)
- Maria Yanova
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia
| | - Evgeniya Stepanova
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia
| | - Diana Maltseva
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia
| | - Alexander Tonevitsky
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
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3
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Ferdousmakan S, Mansourian D, Seyedi Asl FS, Fathi Z, Maleki-Sheikhabadi F, Afjadi MN, Zalpoor H. Autophagy induced by metabolic processes leads to solid tumor cell metastatic dormancy and recurrence. Med Oncol 2025; 42:62. [PMID: 39899220 DOI: 10.1007/s12032-025-02607-6] [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: 10/22/2024] [Accepted: 01/13/2025] [Indexed: 02/04/2025]
Abstract
A crucial cellular mechanism that has a complex impact on the biology of cancer, particularly in solid tumors, is autophagy. This review explores how metabolic processes trigger autophagy, which helps metastatic tumor cells go dormant and recur. During metastasis, tumor cells frequently encounter severe stressors, such as low oxygen levels and nutritional deprivation, which causes them to activate autophagy as a survival tactic. This process allows cancer stem cells (CSCs) to withstand severe conditions while also preserving their features. After years of dormancy, dormant disseminated tumor cells (DTCs) may reappear as aggressive metastatic cancers. The capacity of autophagy to promote resistance to treatments and avoid immune detection is intimately related to this phenomenon. According to recent research, autophagy promotes processes, such as the epithelial-to-mesenchymal transition (EMT) and helps build a pre-metastatic niche, which makes treatment strategies more challenging. Autophagy may be a promising therapeutic target because of its dual function as a tumor suppressor in early-stage cancer and a survival promoter in advanced stages. To effectively treat metastatic diseases, it is crucial to comprehend how metabolic processes interact with autophagy and affect tumor behavior. In order to find novel therapeutic approaches that can interfere with these processes and improve patient outcomes, this study highlights the critical need for additional investigation into the mechanisms by which autophagy controls tumor dormancy and recurrence.
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Affiliation(s)
- Saeid Ferdousmakan
- Department of Pharmacy Practice, Nargund College of Pharmacy, Bangalore, 560085, India
| | - Dorrin Mansourian
- Faculty of Pharmacy, Eastern Mediterranean University, Gazimagusa TRNC via Mersin 10, Mersin, Turkey
| | | | - Zeinab Fathi
- Medical School, Tehran University of Medical Sciences, Tehran, Iran
| | - Fahimeh Maleki-Sheikhabadi
- Department of Hematology and Blood Banking, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohsen Nabi Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Hamidreza Zalpoor
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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4
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Bustos G, Ahumada-Castro U, Silva-Pavez E, Huerta H, Puebla A, Quezada C, Morgado-Cáceres P, Casanova-Canelo C, Smith-Cortinez N, Podunavac M, Oyarce C, Lladser A, Farias P, Lovy A, Molgó J, Torres VA, Zakarian A, Cárdenas JC. The IP 3R inhibitor desmethylxestospongin B reduces tumor cell migration, invasion and metastasis by impairing lysosome acidification and β1-integrin recycling. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167557. [PMID: 39486657 DOI: 10.1016/j.bbadis.2024.167557] [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: 04/19/2024] [Revised: 09/26/2024] [Accepted: 10/28/2024] [Indexed: 11/04/2024]
Abstract
Cancer is the second leading cause of death worldwide. >90 % of cancer-related deaths are due to metastasis, a process that depends on the ability of cancer cells to leave the primary tumor, migrate, and colonize different tissues. Inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ signaling plays an essential role in maintaining the homeostasis of cancer cells and the sustained proliferation. Desmethylxestospongin B (dmXeB) is a specific inhibitor of the IP3R that selectively arrests cell proliferation and promotes cancer cell death at high concentrations. However, whether migration, invasion and metastasis can be affected by this drug is unknown. Here, by using the highly metastatic triple negative breast cancer (TNBC) cell line MDA-MB-231, we demonstrate that a prolonged inhibition of IP3R-mediated Ca2+ signals with dmXeB significantly reduces cell migration and invasion in vitro and metastasis in vivo. We found that this phenomenon was independent of the bioenergetic control of IP3R over the mitochondria and AMPK activation. Furthermore, employing a tandem LC3-GFP-mcherry assay, we found that prolonged inhibition of IP3R with dmXeB leads to diminished autophagic flux. This reduction can be attributed to impaired lysosomal acidification, as evidenced by assessments using DQ-BSA and pHrodo. Since cell migration requires appropriate assembly and disassembly of focal adhesions, along with the internalization and recycling of integrins via autophagy, we explored the dependency of integrin recycling from autophagosomes, finding that IP3R inhibition with dmXeB impaired the recycling of β1-integrins, which accumulated within autophagosomes. Our findings reveal an unexpected effect of IP3R inhibition with dmXeB in cancer cells that could represent a novel therapeutic strategy for the treatment of cancer metastasis.
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Affiliation(s)
- Galdo Bustos
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile; Geroscience Center for Brain Health and Metabolism, Santiago 8580745, Chile
| | - Ulises Ahumada-Castro
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile; Geroscience Center for Brain Health and Metabolism, Santiago 8580745, Chile
| | - Eduardo Silva-Pavez
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile
| | - Hernán Huerta
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile; Geroscience Center for Brain Health and Metabolism, Santiago 8580745, Chile
| | - Andrea Puebla
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile; Geroscience Center for Brain Health and Metabolism, Santiago 8580745, Chile
| | - Camila Quezada
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile; Geroscience Center for Brain Health and Metabolism, Santiago 8580745, Chile
| | - Pablo Morgado-Cáceres
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile; Geroscience Center for Brain Health and Metabolism, Santiago 8580745, Chile
| | - César Casanova-Canelo
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile; Geroscience Center for Brain Health and Metabolism, Santiago 8580745, Chile
| | - Natalia Smith-Cortinez
- Department of Gastroenterology and Hepatology, UMCG, University of Groningen, Netherlands
| | - Maša Podunavac
- Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, CA 93106, USA
| | - Cesar Oyarce
- Department of Medical Microbiology and Infection Prevention, Tumor Virology and Cancer Immunotherapy, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Alvaro Lladser
- Centro Cientifico y Tecnologico de Excelencia Ciencia & Vida, Fundación Ciencia and Vida, Chile; Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Paula Farias
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile; Geroscience Center for Brain Health and Metabolism, Santiago 8580745, Chile
| | - Alenka Lovy
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile; Geroscience Center for Brain Health and Metabolism, Santiago 8580745, Chile
| | - Jordi Molgó
- Université Paris-Saclay, CEA, Département Médicaments et Technologies pour la Santé, Service d'Ingénierie Moléculaire pour la Santé (SIMoS), Equipe Mixte de Recherche CNRS 9004, F-91191 Gif-sur-Yvette, France
| | - Vicente A Torres
- Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Chile; Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago 8380453, Chile; Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, Santiago, Chile
| | - Armen Zakarian
- Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, CA 93106, USA
| | - J César Cárdenas
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile; Geroscience Center for Brain Health and Metabolism, Santiago 8580745, Chile; Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, CA 93106, USA; The Buck Institute for Research on Aging, Novato, USA.
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Raza S, Siddiqui JA, Srivastava A, Chattopadhyay N, Sinha RA, Chakravarti B. Autophagy as a Therapeutic Target in Breast Tumors: The Cancer stem cell perspective. AUTOPHAGY REPORTS 2024; 3:27694127.2024.2358648. [PMID: 39006309 PMCID: PMC7616179 DOI: 10.1080/27694127.2024.2358648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 05/07/2024] [Accepted: 05/16/2024] [Indexed: 07/16/2024]
Abstract
Breast cancer is a heterogeneous disease, with a subpopulation of tumor cells known as breast cancer stem cells (BCSCs) with self-renewal and differentiation abilities that play a critical role in tumor initiation, progression, and therapy resistance. The tumor microenvironment (TME) is a complex area where diverse cancer cells reside creating a highly interactive environment with secreted factors, and the extracellular matrix. Autophagy, a cellular self-digestion process, influences dynamic cellular processes in the tumor TME integrating diverse signals that regulate tumor development and heterogeneity. Autophagy acts as a double-edged sword in the breast TME, with both tumor-promoting and tumor-suppressing roles. Autophagy promotes breast tumorigenesis by regulating tumor cell survival, migration and invasion, metabolic reprogramming, and epithelial-mesenchymal transition (EMT). BCSCs harness autophagy to maintain stemness properties, evade immune surveillance, and resist therapeutic interventions. Conversely, excessive, or dysregulated autophagy may lead to BCSC differentiation or cell death, offering a potential avenue for therapeutic exploration. The molecular mechanisms that regulate autophagy in BCSCs including the mammalian target of rapamycin (mTOR), AMPK, and Beclin-1 signaling pathways may be potential targets for pharmacological intervention in breast cancer. This review provides a comprehensive overview of the relationship between autophagy and BCSCs, highlighting recent advancements in our understanding of their interplay. We also discuss the current state of autophagy-targeting agents and their preclinical and clinical development in BCSCs.
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Affiliation(s)
- Sana Raza
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow226014, India
| | - Jawed Akhtar Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA
| | - Anubhav Srivastava
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow226014, India
| | - Naibedya Chattopadhyay
- Division of Endocrinology and Center for Research in Anabolic Skeletal Target in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Rohit Anthony Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow226014, India
| | - Bandana Chakravarti
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow226014, India
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Singh MK, Han S, Kim S, Kang I. Targeting Lipid Metabolism in Cancer Stem Cells for Anticancer Treatment. Int J Mol Sci 2024; 25:11185. [PMID: 39456967 PMCID: PMC11508222 DOI: 10.3390/ijms252011185] [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: 09/06/2024] [Revised: 10/14/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024] Open
Abstract
Cancer stem cells (CSCs), or tumor-initiating cells (TICs), are small subpopulations (0.0001-0.1%) of cancer cells that are crucial for cancer relapse and therapy resistance. The elimination of each CSC is essential for achieving long-term remission. Metabolic reprogramming, particularly lipids, has a significant impact on drug efficacy by influencing drug diffusion, altering membrane permeability, modifying mitochondrial function, and adjusting the lipid composition within CSCs. These changes contribute to the development of chemoresistance in various cancers. The intricate relationship between lipid metabolism and drug resistance in CSCs is an emerging area of research, as different lipid species play essential roles in multiple stages of autophagy. However, the link between autophagy and lipid metabolism in the context of CSC regulation remains unclear. Understanding the interplay between autophagy and lipid reprogramming in CSCs could lead to the development of new approaches for enhancing therapies and reducing tumorigenicity in these cells. In this review, we explore the latest findings on lipid metabolism in CSCs, including the role of key regulatory enzymes, inhibitors, and the contribution of autophagy in maintaining lipid homeostasis. These recent findings may provide critical insights for identifying novel pharmacological targets for effective anticancer treatment.
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Affiliation(s)
- Manish Kumar Singh
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sunhee Han
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sungsoo Kim
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Insug Kang
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
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Niharika, Garg M. Understanding the autophagic functions in cancer stem cell maintenance and therapy resistance. Expert Rev Mol Med 2024; 26:e23. [PMID: 39375840 PMCID: PMC11488345 DOI: 10.1017/erm.2024.23] [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: 08/29/2023] [Revised: 12/25/2023] [Accepted: 06/25/2024] [Indexed: 10/09/2024]
Abstract
Complex tumour ecosystem comprising tumour cells and its associated tumour microenvironment (TME) constantly influence the tumoural behaviour and ultimately impact therapy failure, disease progression, recurrence and poor overall survival of patients. Crosstalk between tumour cells and TME amplifies the complexity by creating metabolic changes such as hypoxic environment and nutrient fluctuations. These changes in TME initiate stem cell-like programmes in cancer cells, contribute to tumoural heterogeneity and increase tumour robustness. Recent studies demonstrate the multifaceted role of autophagy in promoting fibroblast production, stemness, cancer cell survival during longer periods of dormancy, eventual growth of metastatic disease and disease resistance. Recent ongoing studies examine autophagy/mitophagy as a powerful survival strategy in response to environmental stress including nutrient deprivation, hypoxia and environmental stress in TME. It prevents irreversible senescence, promotes dormant stem-like state, induces epithelial-mesenchymal transition and increases migratory and invasive potential of tumour cells. The present review discusses various theories and mechanisms behind the autophagy-dependent induction of cancer stem cell (CSC) phenotype. Given the role of autophagic functions in CSC aggressiveness and therapeutic resistance, various mechanisms and studies based on suppressing cellular plasticity by blocking autophagy as a powerful therapeutic strategy to kill tumour cells are discussed.
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Affiliation(s)
- Niharika
- Department of Biochemistry, University of Lucknow, Lucknow 226007, India
| | - Minal Garg
- Department of Biochemistry, University of Lucknow, Lucknow 226007, India
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Maroni P, Lombardi G, Ferraretto A, Bendinelli P. Immunohistochemistry analysis of autophagy-related proteins Beclin-1, p62/SQSTM1, and LC3B in breast carcinoma progression to bone metastasis. Pathol Res Pract 2024; 260:155414. [PMID: 38901141 DOI: 10.1016/j.prp.2024.155414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 06/04/2024] [Accepted: 06/16/2024] [Indexed: 06/22/2024]
Abstract
Autophagy is a catabolic pathway involved both in tissue homeostasis and in cellular response to stress. The precise role of autophagy in cancer is still undefined and seems to depend on the tumor stage, appearing tumor-suppressive in physiological conditions and helpful to tumor progression in the established tumor. Here we analyzed by immunohistochemistry Beclin-1, p62, and LC3B, autophagic markers, in human specimens of normal breast, bone metastasis together with pair-matched invasive breast carcinoma of no special type (IBC-NST) as well as non-metastatic breast carcinoma, to disclose the possibility that they could be early prognostic indicators of the evolution of the disease toward the worst outcome. Different regions of metastatic carcinomas, i.e., areas adjacent to the tumor without signs of neoplastic growth, dysplastic lesions, and areas with invasive growth were considered. The pattern of autophagic parameters showed differences among the stages of breast carcinoma progression with a trend that indicated the activation of autophagic process in normal breast (Beclin-1 more elevated than p62), a pattern that was maintained in non-metastatic carcinoma. As the neoplasia proceeds with malignancy, the modification of the pattern of expression of autophagic markers (low ratio between Beclin-1 and p62) in areas of invasive growth of carcinomas suggested inhibition of the process. Of note, the parameters showed a different pattern in bone metastasis with respect to bone metastatic (bm)-IBC-NST, suggesting the reactivation of the autophagic process in the new growth site, helpful to the colonization. The course of autophagy markers during tumor progression could have a prognostic value towards bone metastasis and reveal different roles of the process in different phases of neoplastic growth. The understanding of the role of autophagy in bone metastasis could disclose new therapeutic targets to improve the conditions of patients.
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Affiliation(s)
- Paola Maroni
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via Cristina Belgioioso 173, Milano 20161, Italy.
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via Cristina Belgioioso 173, Milano 20161, Italy; Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland
| | - Anita Ferraretto
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via L. Mangiagalli 31, Milano 20133, Italy
| | - Paola Bendinelli
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via L. Mangiagalli 31, Milano 20133, Italy
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Du J, Qin H. Lipid metabolism dynamics in cancer stem cells: potential targets for cancers. Front Pharmacol 2024; 15:1367981. [PMID: 38994204 PMCID: PMC11236562 DOI: 10.3389/fphar.2024.1367981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 06/10/2024] [Indexed: 07/13/2024] Open
Abstract
Cancer stem cells (CSCs) represent a small subset of heterogeneous cells within tumors that possess the ability to self-renew and initiate tumorigenesis. They serve as potential drivers for tumor initiation, metastasis, recurrence, and drug resistance. Recent research has demonstrated that the stemness preservation of CSCs is heavily reliant on their unique lipid metabolism alterations, enabling them to maintain their own environmental homeostasis through various mechanisms. The primary objectives involve augmenting intracellular fatty acid (FA) content to bolster energy supply, promoting β-oxidation of FA to optimize energy utilization, and elevating the mevalonate (MVA) pathway for efficient cholesterol synthesis. Additionally, lipid droplets (LDs) can serve as alternative energy sources in the presence of glycolysis blockade in CSCs, thereby safeguarding FA from peroxidation. Furthermore, the interplay between autophagy and lipid metabolism facilitates rapid adaptation of CSCs to the harsh microenvironment induced by chemotherapy. In this review, we comprehensively review recent studies pertaining to lipid metabolism in CSCs and provide a concise overview of the indispensable role played by LDs, FA, cholesterol metabolism, and autophagy in maintaining the stemness of CSCs.
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Affiliation(s)
- Juan Du
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Hai Qin
- Department of Clinical Laboratory, Beijing Jishuitan Hospital Guizhou Hospital, Guiyang, China
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10
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Ayub A, Hasan MK, Mahmud Z, Hossain MS, Kabir Y. Dissecting the multifaceted roles of autophagy in cancer initiation, growth, and metastasis: from molecular mechanisms to therapeutic applications. Med Oncol 2024; 41:183. [PMID: 38902544 DOI: 10.1007/s12032-024-02417-2] [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: 04/12/2024] [Accepted: 05/28/2024] [Indexed: 06/22/2024]
Abstract
Autophagy is a cytoplasmic defense mechanism that cells use to break and reprocess their intracellular components. This utilization of autophagy is regarded as a savior in nutrient-deficient and other stressful conditions. Hence, autophagy keeps contact with and responds to miscellaneous cellular tensions and diverse pathways of signal transductions, such as growth signaling and cellular death. Importantly, autophagy is regarded as an effective tumor suppressor because regular autophagic breakdown is essential for cellular maintenance and minimizing cellular damage. However, paradoxically, autophagy has also been observed to promote the events of malignancies. This review discussed the dual role of autophagy in cancer, emphasizing its influence on tumor survival and progression. Possessing such a dual contribution to the malignant establishment, the prevention of autophagy can potentially advocate for the advancement of malignant transformation. In contrast, for the context of the instituted tumor, the agents of preventing autophagy potently inhibit the advancement of the tumor. Key regulators, including calpain 1, mTORC1, and AMPK, modulate autophagy in response to nutritional conditions and stress. Oncogenic mutations like RAS and B-RAF underscore autophagy's pivotal role in cancer development. The review also delves into autophagy's context-dependent roles in tumorigenesis, metastasis, and the tumor microenvironment (TME). It also discusses the therapeutic effectiveness of autophagy for several cancers. The recent implication of autophagy in the control of both innate and antibody-mediated immune systems made it a center of attention to evaluating its role concerning tumor antigens and treatments of cancer.
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Affiliation(s)
- Afia Ayub
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur, 1704, Bangladesh
| | - Md Kamrul Hasan
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur, 1704, Bangladesh.
- Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St. W., Hamilton, L8S 4K1, Canada.
- Department of Public Health, North South University, Dhaka, Bangladesh.
| | - Zimam Mahmud
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
| | - Md Sabbir Hossain
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur, 1704, Bangladesh
| | - Yearul Kabir
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
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Tiwari M, Srivastava P, Abbas S, Jegatheesan J, Ranjan A, Sharma S, Maurya VP, Saxena AK, Sharma LK. Emerging Role of Autophagy in Governing Cellular Dormancy, Metabolic Functions, and Therapeutic Responses of Cancer Stem Cells. Cells 2024; 13:447. [PMID: 38474411 PMCID: PMC10930960 DOI: 10.3390/cells13050447] [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: 01/12/2024] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024] Open
Abstract
Tumors are composed of heterogeneous populations of dysregulated cells that grow in specialized niches that support their growth and maintain their properties. Tumor heterogeneity and metastasis are among the major hindrances that exist while treating cancer patients, leading to poor clinical outcomes. Although the factors that determine tumor complexity remain largely unknown, several genotypic and phenotypic changes, including DNA mutations and metabolic reprograming provide cancer cells with a survival advantage over host cells and resistance to therapeutics. Furthermore, the presence of a specific population of cells within the tumor mass, commonly known as cancer stem cells (CSCs), is thought to initiate tumor formation, maintenance, resistance, and recurrence. Therefore, these CSCs have been investigated in detail recently as potential targets to treat cancer and prevent recurrence. Understanding the molecular mechanisms involved in CSC proliferation, self-renewal, and dormancy may provide important clues for developing effective therapeutic strategies. Autophagy, a catabolic process, has long been recognized to regulate various physiological and pathological processes. In addition to regulating cancer cells, recent studies have identified a critical role for autophagy in regulating CSC functions. Autophagy is activated under various adverse conditions and promotes cellular maintenance, survival, and even cell death. Thus, it is intriguing to address whether autophagy promotes or inhibits CSC functions and whether autophagy modulation can be used to regulate CSC functions, either alone or in combination. This review describes the roles of autophagy in the regulation of metabolic functions, proliferation and quiescence of CSCs, and its role during therapeutic stress. The review further highlights the autophagy-associated pathways that could be used to regulate CSCs. Overall, the present review will help to rationalize various translational approaches that involve autophagy-mediated modulation of CSCs in controlling cancer progression, metastasis, and recurrence.
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Affiliation(s)
- Meenakshi Tiwari
- Department of Biochemistry, All India Institute of Medical Science, Patna 801507, India
| | - Pransu Srivastava
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Science, Lucknow 226014, India
| | - Sabiya Abbas
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Science, Lucknow 226014, India
| | - Janani Jegatheesan
- Department of Biochemistry, All India Institute of Medical Science, Patna 801507, India
| | - Ashish Ranjan
- Department of Biochemistry, All India Institute of Medical Science, Patna 801507, India
| | - Sadhana Sharma
- Department of Biochemistry, All India Institute of Medical Science, Patna 801507, India
| | - Ved Prakash Maurya
- Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Ajit Kumar Saxena
- Department of Pathology/Lab Medicine, All India Institute of Medical Science, Patna 801507, India
| | - Lokendra Kumar Sharma
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Science, Lucknow 226014, India
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12
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Guil-Luna S, Sanchez-Montero MT, Rodríguez-Ariza A. S-Nitrosylation at the intersection of metabolism and autophagy: Implications for cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:189012. [PMID: 37918453 DOI: 10.1016/j.bbcan.2023.189012] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/26/2023] [Accepted: 10/20/2023] [Indexed: 11/04/2023]
Abstract
Metabolic plasticity, which determines tumour growth and metastasis, is now understood to be a flexible and context-specific process in cancer metabolism. One of the major pathways contributing to metabolic adaptations in eucaryotic cells is autophagy, a cellular degradation and recycling process that is activated during periods of starvation or stress to maintain metabolite and biosynthetic intermediate levels. Consequently, there is a close association between the metabolic adaptive capacity of tumour cells and autophagy-related pathways in cancer. Additionally, nitric oxide regulates protein function and signalling through S-nitrosylation, a post-translational modification that can also impact metabolism and autophagy. The primary objective of this review is to provide an up-to-date overview of the role of S-nitrosylation at the intersection of metabolism and autophagy in cancer. First, we will outline the involvement of S-nitrosylation in the metabolic adaptations that occur in tumours. Then, we will discuss the multifaceted role of autophagy in cancer, the interplay between metabolism and autophagy during tumour progression, and the contribution of S-nitrosylation to autophagic dysregulation in cancer. Finally, we will present insights into relevant therapeutic aspects and discuss prospects for the future.
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Affiliation(s)
- Silvia Guil-Luna
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain; Department of Comparative Anatomy and Pathology, Faculty of Veterinary Medicine of Córdoba, University of Córdoba, Córdoba, Spain
| | | | - Antonio Rodríguez-Ariza
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain; Medical Oncology Department, Reina Sofía University Hospital, Córdoba, Spain.
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13
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Reisenauer KN, Aroujo J, Tao Y, Ranganathan S, Romo D, Taube JH. Therapeutic vulnerabilities of cancer stem cells and effects of natural products. Nat Prod Rep 2023; 40:1432-1456. [PMID: 37103550 PMCID: PMC10524555 DOI: 10.1039/d3np00002h] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
Abstract
Covering: 1995 to 2022Tumors possess both genetic and phenotypic heterogeneity leading to the survival of subpopulations post-treatment. The term cancer stem cells (CSCs) describes a subpopulation that is resistant to many types of chemotherapy and which also possess enhanced migratory and anchorage-independent growth capabilities. These cells are enriched in residual tumor material post-treatment and can serve as the seed for future tumor re-growth, at both primary and metastatic sites. Elimination of CSCs is a key goal in enhancing cancer treatment and may be aided by application of natural products in conjunction with conventional treatments. In this review, we highlight molecular features of CSCs and discuss synthesis, structure-activity relationships, derivatization, and effects of six natural products with anti-CSC activity.
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Affiliation(s)
| | - Jaquelin Aroujo
- Department of Chemistry and Biochemistry, Baylor Univesrity, Waco, TX, USA
| | - Yongfeng Tao
- Department of Chemistry and Biochemistry, Baylor Univesrity, Waco, TX, USA
| | | | - Daniel Romo
- Department of Chemistry and Biochemistry, Baylor Univesrity, Waco, TX, USA
| | - Joseph H Taube
- Department of Biology, Baylor University, Waco, TX, USA.
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
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14
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Nieto-Torres JL, Zaretski S, Liu T, Adams PD, Hansen M. Post-translational modifications of ATG8 proteins - an emerging mechanism of autophagy control. J Cell Sci 2023; 136:jcs259725. [PMID: 37589340 PMCID: PMC10445744 DOI: 10.1242/jcs.259725] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2023] Open
Abstract
Autophagy is a recycling mechanism involved in cellular homeostasis with key implications for health and disease. The conjugation of the ATG8 family proteins, which includes LC3B (also known as MAP1LC3B), to autophagosome membranes, constitutes a hallmark of the canonical autophagy process. After ATG8 proteins are conjugated to the autophagosome membranes via lipidation, they orchestrate a plethora of protein-protein interactions that support key steps of the autophagy process. These include binding to cargo receptors to allow cargo recruitment, association with proteins implicated in autophagosome transport and autophagosome-lysosome fusion. How these diverse and critical protein-protein interactions are regulated is still not well understood. Recent reports have highlighted crucial roles for post-translational modifications of ATG8 proteins in the regulation of ATG8 functions and the autophagy process. This Review summarizes the main post-translational regulatory events discovered to date to influence the autophagy process, mostly described in mammalian cells, including ubiquitylation, acetylation, lipidation and phosphorylation, as well as their known contributions to the autophagy process, physiology and disease.
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Affiliation(s)
- Jose L. Nieto-Torres
- Sanford Burnham Prebys Medical Discovery Institute, Program of Development, Aging, and Regeneration, La Jolla, CA 92037, USA
- Department of Biomedical Sciences, School of Health Sciences and Veterinary, Universidad Cardenal Herrera-CEU, CEU Universities, 46113 Moncada, Spain
| | - Sviatlana Zaretski
- Sanford Burnham Prebys Medical Discovery Institute, Program of Development, Aging, and Regeneration, La Jolla, CA 92037, USA
| | - Tianhui Liu
- Sanford Burnham Prebys Medical Discovery Institute, Program of Development, Aging, and Regeneration, La Jolla, CA 92037, USA
| | - Peter D. Adams
- Sanford Burnham Prebys Medical Discovery Institute, Program of Development, Aging, and Regeneration, La Jolla, CA 92037, USA
| | - Malene Hansen
- Sanford Burnham Prebys Medical Discovery Institute, Program of Development, Aging, and Regeneration, La Jolla, CA 92037, USA
- The Buck Institute for Aging Research, Novato, CA 94945, USA
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15
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Chakravarti B, Akhtar Siddiqui J, Anthony Sinha R, Raza S. Targeting autophagy and lipid metabolism in cancer stem cells. Biochem Pharmacol 2023; 212:115550. [PMID: 37060962 DOI: 10.1016/j.bcp.2023.115550] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 04/17/2023]
Abstract
Cancer stem cells (CSCs) are a subset of cancer cells with self-renewal ability and tumor initiating properties. Unlike the other non-stem cancer cells, CSCs resist traditional therapy and remain a major cause of disease relapse. With the recent advances in metabolomics, various studies have demonstrated that CSCs have distinct metabolic properties. Metabolic reprogramming in CSCs contributes to self-renewal and maintenance of stemness. Accumulating evidence suggests that rewiring of energy metabolism is a key player that enables to meet energy demands, maintains stemness, and sustains cancer growth and invasion. CSCs use various mechanisms such as increased glycolysis, redox signaling, and autophagy modulation to overcome nutritional deficiency and sustain cell survival. The alterations in lipid metabolism acquired by the CSCs support biomass production through increased dependence on fatty acid synthesis and β-oxidation, and contribute to oncogenic signaling pathways. This review summarizes our current understanding of lipid metabolism in CSCs and how pharmacological regulation of autophagy and lipid metabolism influences CSC phenotype. Increased dependence on lipid metabolism appears as an attractive strategy to eliminate CSCs using therapeutic agents that specifically target CSCs based on their modulation of lipid metabolism.
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Affiliation(s)
- Bandana Chakravarti
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226014, India
| | - Jawed Akhtar Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Rohit Anthony Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226014, India.
| | - Sana Raza
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226014, India.
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16
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Assi M, Kimmelman AC. Impact of context-dependent autophagy states on tumor progression. NATURE CANCER 2023; 4:596-607. [PMID: 37069394 PMCID: PMC10542907 DOI: 10.1038/s43018-023-00546-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 03/20/2023] [Indexed: 04/19/2023]
Abstract
Macroautophagy is a cellular quality-control process that degrades proteins, protein aggregates and damaged organelles. Autophagy plays a fundamental role in cancer where, in the presence of stressors (for example, nutrient starvation, hypoxia, mechanical pressure), tumor cells activate it to degrade intracellular substrates and provide energy. Cell-autonomous autophagy in tumor cells and cell-nonautonomous autophagy in the tumor microenvironment and in the host converge on mechanisms that modulate metabolic fitness, DNA integrity and immune escape and, consequently, support tumor growth. In this Review, we will discuss insights into the tumor-modulating roles of autophagy in different contexts and reflect on how future studies using physiological culture systems may help to understand the complexity and open new therapeutic avenues.
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Affiliation(s)
- Mohamad Assi
- Department of Radiation Oncology, New York University Langone Health, New York, NY, USA
- Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA
| | - Alec C Kimmelman
- Department of Radiation Oncology, New York University Langone Health, New York, NY, USA.
- Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA.
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17
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Hashemi M, Paskeh MDA, Orouei S, Abbasi P, Khorrami R, Dehghanpour A, Esmaeili N, Ghahremanzade A, Zandieh MA, Peymani M, Salimimoghadam S, Rashidi M, Taheriazam A, Entezari M, Hushmandi K. Towards dual function of autophagy in breast cancer: A potent regulator of tumor progression and therapy response. Biomed Pharmacother 2023; 161:114546. [PMID: 36958191 DOI: 10.1016/j.biopha.2023.114546] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 03/11/2023] [Accepted: 03/14/2023] [Indexed: 03/25/2023] Open
Abstract
As a devastating disease, breast cancer has been responsible for decrease in life expectancy of females and its morbidity and mortality are high. Breast cancer is the most common tumor in females and its treatment has been based on employment of surgical resection, chemotherapy and radiotherapy. The changes in biological behavior of breast tumor relies on genomic and epigenetic mutations and depletions as well as dysregulation of molecular mechanisms that autophagy is among them. Autophagy function can be oncogenic in increasing tumorigenesis, and when it has pro-death function, it causes reduction in viability of tumor cells. The carcinogenic function of autophagy in breast tumor is an impediment towards effective therapy of patients, as it can cause drug resistance and radio-resistance. The important hallmarks of breast tumor such as glucose metabolism, proliferation, apoptosis and metastasis can be regulated by autophagy. Oncogenic autophagy can inhibit apoptosis, while it promotes stemness of breast tumor. Moreover, autophagy demonstrates interaction with tumor microenvironment components such as macrophages and its level can be regulated by anti-tumor compounds in breast tumor therapy. The reasons of considering autophagy in breast cancer therapy is its pleiotropic function, dual role (pro-survival and pro-death) and crosstalk with important molecular mechanisms such as apoptosis. Moreover, current review provides a pre-clinical and clinical evaluation of autophagy in breast tumor.
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Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mahshid Deldar Abad Paskeh
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sima Orouei
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Pegah Abbasi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ramin Khorrami
- Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Amir Dehghanpour
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Negin Esmaeili
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Azin Ghahremanzade
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari 4815733971, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari 4815733971, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
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18
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Saran U, Chandrasekaran B, Tyagi A, Shukla V, Singh A, Sharma AK, Damodaran C. A small molecule inhibitor of Notch1 modulates stemness and suppresses breast cancer cell growth. Front Pharmacol 2023; 14:1150774. [PMID: 36909163 PMCID: PMC9998682 DOI: 10.3389/fphar.2023.1150774] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 02/10/2023] [Indexed: 03/14/2023] Open
Abstract
Although breast cancer stem cells (BCSCs) are well characterized, molecularly targeting and eradicating this sub-population remains a challenge in the clinic. Recent studies have explored several signaling pathways that govern stem cell activation: We and others established that the Notch1 signaling plays a significant role in the proliferation, survival, and differentiation of BCSCs. Earlier, we reported that a newly developed small molecule, ASR490, binds to the negative regulatory region (NRR: The activation switch of the Notch receptor) of Notch1. In vitro results demonstrated that ASR490 significantly inhibited BCSCs (ALDH+ and CD44+/CD24-) and breast cancer (BC) growth at nM concentrations, and subsequently inhibited the colony- and mammosphere-forming abilities of BCSCs and BCs. ASR490 downregulated the expressions of Notch1 intracellular domain (NICD: The active form of Notch1) and its downstream effectors Hey1 and HES1. Inhibition of Notch1-NICD facilitated autophagy-mediated growth inhibition by triggering the fusion of autophagosome and autolysosome in BCSCs. ASR490 was found to be non-toxic to healthy cells as compared to existing Notch1 inhibitors. Moreover, oral administration of ASR490 abrogated BCSC and BC tumor growth in the in vivo xenograft models. Together our results indicate that ASR490 is a potential therapeutic agent that inhibits BC tumor growth by targeting and abolishing Notch1 signaling in BCSCs and BC cells.
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Affiliation(s)
- Uttara Saran
- Texas A&M University, College Station, TX, United States
| | | | - Ashish Tyagi
- Texas A&M University, College Station, TX, United States
| | - Vaibhav Shukla
- Texas A&M University, College Station, TX, United States
| | - Amandeep Singh
- Penn State Cancer Institute, College of Medicine, The Pennsylvania State University, Hershey, PA, United States
| | - Arun K. Sharma
- Penn State Cancer Institute, College of Medicine, The Pennsylvania State University, Hershey, PA, United States
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19
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The Role of Autophagy in Breast Cancer Metastasis. Biomedicines 2023; 11:biomedicines11020618. [PMID: 36831154 PMCID: PMC9953203 DOI: 10.3390/biomedicines11020618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/07/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Patient morbidity and mortality is significantly increased in metastatic breast cancer. The metastasis process of breast cancer is very complicated and is delicately controlled by various factors. Autophagy is one of the important regulatory factors affecting metastasis in breast cancer by engaging in cell mobility, metabolic adaptation, tumor dormancy, and cancer stem cells. Here, we discuss the effects of autophagy on metastasis in breast cancer and assess the potential use of autophagy modulators for metastasis treatment.
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20
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Chaudhary A, Raza SS, Haque R. Transcriptional factors targeting in cancer stem cells for tumor modulation. Semin Cancer Biol 2023; 88:123-137. [PMID: 36603792 DOI: 10.1016/j.semcancer.2022.12.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/03/2023]
Abstract
Cancer Stem Cells (CSCs) are now considered the primary "seeds" for the onset, development, metastasis, and recurrence of tumors. Despite therapeutic breakthroughs, cancer remains the leading cause of death worldwide. This is because the tumor microenvironment contains a key population of cells known as CSCs, which promote tumor aggression. CSCs are self-renewing cells that aid tumor recurrence by promoting tumor growth and persisting in patients after many traditional cancer treatments. According to reports, numerous transcription factors (TF) play a key role in maintaining CSC pluripotency and its self-renewal property. The understanding of the functions, structures, and interactional dynamics of these transcription factors with DNA has modified the hypothesis, paving the way for novel transcription factor-targeted therapies. These TFs, which are crucial and are required by cancer cells, play a vital function in the etiology of human cancer. Such CSC TFs will help with gene expression profiling, which provides crucial data for predicting the prognosis of patients. To overcome anti-cancer medication resistance and completely eradicate cancer, a potent therapy combining TFs-based CSC targets with traditional chemotherapy may be developed. In order to develop therapies that could eliminate CSCs, we here concentrated on the effect of TFs and other components of signalling pathways on cancer stemness.
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Affiliation(s)
- Archana Chaudhary
- Department of Biotechnology, School of Earth Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India
| | - Syed Shadab Raza
- Laboratory for Stem Cell & Restorative Neurology, Era's Lucknow Medical College and Hospital, Era University, Lucknow, India
| | - Rizwanul Haque
- Department of Biotechnology, School of Earth Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India.
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21
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Lo Iacono M, Gaggianesi M, Bianca P, Brancato OR, Muratore G, Modica C, Roozafzay N, Shams K, Colarossi L, Colarossi C, Memeo L, Turdo A, Veschi V, Di Franco S, Todaro M, Stassi G. Destroying the Shield of Cancer Stem Cells: Natural Compounds as Promising Players in Cancer Therapy. J Clin Med 2022; 11:6996. [PMID: 36498571 PMCID: PMC9737492 DOI: 10.3390/jcm11236996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/21/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
In a scenario where eco-sustainability and a reduction in chemotherapeutic drug waste are certainly a prerogative to safeguard the biosphere, the use of natural products (NPs) represents an alternative therapeutic approach to counteract cancer diseases. The presence of a heterogeneous cancer stem cell (CSC) population within a tumor bulk is related to disease recurrence and therapy resistance. For this reason, CSC targeting presents a promising strategy for hampering cancer recurrence. Increasing evidence shows that NPs can inhibit crucial signaling pathways involved in the maintenance of CSC stemness and sensitize CSCs to standard chemotherapeutic treatments. Moreover, their limited toxicity and low costs for large-scale production could accelerate the use of NPs in clinical settings. In this review, we will summarize the most relevant studies regarding the effects of NPs derived from major natural sources, e.g., food, botanical, and marine species, on CSCs, elucidating their use in pre-clinical and clinical studies.
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Affiliation(s)
- Melania Lo Iacono
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Miriam Gaggianesi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Paola Bianca
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Ornella Roberta Brancato
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Giampaolo Muratore
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Chiara Modica
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Narges Roozafzay
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Kimiya Shams
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Lorenzo Colarossi
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Viagrande, 95029 Catania, Italy
| | - Cristina Colarossi
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Viagrande, 95029 Catania, Italy
| | - Lorenzo Memeo
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Viagrande, 95029 Catania, Italy
| | - Alice Turdo
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Veronica Veschi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Simone Di Franco
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Matilde Todaro
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Giorgio Stassi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
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22
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Khan SU, Fatima K, Aisha S, Hamza B, Malik F. Redox balance and autophagy regulation in cancer progression and their therapeutic perspective. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:12. [PMID: 36352310 DOI: 10.1007/s12032-022-01871-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 09/30/2022] [Indexed: 11/10/2022]
Abstract
Cellular ROS production participates in various cellular functions but its accumulation decides the cell fate. Malignant cells have higher levels of ROS and active antioxidant machinery, a characteristic hallmark of cancer with an outcome of activation of stress-induced pathways like autophagy. Autophagy is an intracellular catabolic process that produces alternative raw materials to meet the energy demand of cells and is influenced by the cellular redox state thus playing a definite role in cancer cell fate. Since damaged mitochondria are the main source of ROS in the cell, however, cancer cells remove them by upregulating the process of mitophagy which is known to play a decisive role in tumorigenesis and tumor progression. Chemotherapy exploits cell machinery which results in the accumulation of toxic levels of ROS in cells resulting in cell death by activating either of the pathways like apoptosis, necrosis, ferroptosis or autophagy in them. So understanding these redox and autophagy regulations offers a promising method to design and develop new cancer therapies that can be very effective and durable for years. This review will give a summary of the current therapeutic molecules targeting redox regulation and autophagy for the treatment of cancer. Further, it will highlight various challenges in developing anticancer agents due to autophagy and ROS regulation in the cell and insights into the development of future therapies.
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Affiliation(s)
- Sameer Ullah Khan
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, 190005, Jammu and Kashmir, India.
- Academy of Scientific and Innovative Research (AcSIR), Sanat Nagar, Ghaziabad, 201002, India.
| | - Kaneez Fatima
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, 190005, Jammu and Kashmir, India
- Academy of Scientific and Innovative Research (AcSIR), Sanat Nagar, Ghaziabad, 201002, India
| | - Shariqa Aisha
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, 190005, Jammu and Kashmir, India
| | - Baseerat Hamza
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, 190005, Jammu and Kashmir, India
| | - Fayaz Malik
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, 190005, Jammu and Kashmir, India.
- Academy of Scientific and Innovative Research (AcSIR), Sanat Nagar, Ghaziabad, 201002, India.
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Stem Cells as Target for Prostate cancer Therapy: Opportunities and Challenges. Stem Cell Rev Rep 2022; 18:2833-2851. [PMID: 35951166 DOI: 10.1007/s12015-022-10437-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2022] [Indexed: 10/15/2022]
Abstract
Cancer stem cells (CSCs) and cells in a cancer stem cell-like (CSCL) state have proven to be responsible for tumor initiation, growth, and relapse in Prostate Cancer (PCa) and other cancers; therefore, new strategies are being developed to target such cellular populations. TLR3 activation-based immunotherapy using Polyinosinic:Polycytidylic acid (PIC) has been proposed to be used as a concomitant strategy to first-line treatment. This strategy is based on the induction of apoptosis and an inflammatory response in tumor cells. In combination with retinoids like 9cRA, this treatment can induce CSCs differentiation and apoptosis. A limitation in the use of this combination is the common decreased expression of TLR3 and its main positive regulator p53. observed in many patients suffering of different cancer types such as PCa. Importantly, human exposure to certain toxicants, such as iAs, not only has proven to enrich CSCs population in an in vitro model of human epithelial prostate cells, but additionally, it can also lead to a decreased p53, TLR3 and RA receptor (RARβ), expression/activation and thus hinder this treatment efficacy. Therefore, here we point out the relevance of evaluating the TLR3 and P53 status in PCa patients before starting an immunotherapy based on the use of PIC +9cRA to determine whether they will be responsive to treatment. Additionally, the use of strategies to overcome the lower TLR3, RARβ or p53 expression in PCa patients, like the inclusion of drugs that increase p53 expression, is encouraged, to potentiate the use of PIC+RA based immunotherapy in these patients.
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Xu L, Zhang J, Sun J, Hou K, Yang C, Guo Y, Liu X, Kalvakolanu DV, Zhang L, Guo B. Epigenetic regulation of cancer stem cells: Shedding light on the refractory/relapsed cancers. Biochem Pharmacol 2022; 202:115110. [PMID: 35640714 DOI: 10.1016/j.bcp.2022.115110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/05/2023]
Abstract
The resistance to drugs, ability to enter quiescence and generate heterogeneous cancer cells, and enhancement of aggressiveness, make cancer stem cells (CSCs) integral part of tumor progression, metastasis and recurrence after treatment. The epigenetic modification machinery is crucial for the viability of CSCs and evolution of aggressive forms of a tumor. These mechanisms can also be targeted by specific drugs, providing a promising approach for blocking CSCs. In this review, we summarize the epigenetic regulatory mechanisms in CSCs which contribute to drug resistance, quiescence and tumor heterogeneity. We also discuss the drugs that can potentially target these processes and data from experimental and clinical studies.
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Affiliation(s)
- Libo Xu
- Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, PR China; Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Jinghua Zhang
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Jicheng Sun
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Kunlin Hou
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Chenxin Yang
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Ying Guo
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Xiaorui Liu
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Dhan V Kalvakolanu
- Greenebaum NCI Comprehensive Cancer Center, Department of Microbiology and Immunology, University of Maryland School Medicine, Baltimore, MD, USA
| | - Ling Zhang
- Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, PR China; Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China.
| | - Baofeng Guo
- Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, PR China.
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Vitto VAM, Bianchin S, Zolondick AA, Pellielo G, Rimessi A, Chianese D, Yang H, Carbone M, Pinton P, Giorgi C, Patergnani S. Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy. Biomedicines 2022; 10:1596. [PMID: 35884904 PMCID: PMC9313210 DOI: 10.3390/biomedicines10071596] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/25/2022] [Accepted: 06/30/2022] [Indexed: 01/18/2023] Open
Abstract
Autophagy is an evolutionarily conserved and tightly regulated process that plays an important role in maintaining cellular homeostasis. It involves regulation of various genes that function to degrade unnecessary or dysfunctional cellular components, and to recycle metabolic substrates. Autophagy is modulated by many factors, such as nutritional status, energy level, hypoxic conditions, endoplasmic reticulum stress, hormonal stimulation and drugs, and these factors can regulate autophagy both upstream and downstream of the pathway. In cancer, autophagy acts as a double-edged sword depending on the tissue type and stage of tumorigenesis. On the one hand, autophagy promotes tumor progression in advanced stages by stimulating tumor growth. On the other hand, autophagy inhibits tumor development in the early stages by enhancing its tumor suppressor activity. Moreover, autophagy drives resistance to anticancer therapy, even though in some tumor types, its activation induces lethal effects on cancer cells. In this review, we summarize the biological mechanisms of autophagy and its dual role in cancer. In addition, we report the current understanding of autophagy in some cancer types with markedly high incidence and/or lethality, and the existing therapeutic strategies targeting autophagy for the treatment of cancer.
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Affiliation(s)
- Veronica Angela Maria Vitto
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Silvia Bianchin
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Alicia Ann Zolondick
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816, USA; (A.A.Z.); (H.Y.); (M.C.)
- Department of Molecular Biosciences and Bioengineering, University of Hawai’i at Manoa, Honolulu, HI 96816, USA
| | - Giulia Pellielo
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Alessandro Rimessi
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Diego Chianese
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Haining Yang
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816, USA; (A.A.Z.); (H.Y.); (M.C.)
| | - Michele Carbone
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816, USA; (A.A.Z.); (H.Y.); (M.C.)
| | - Paolo Pinton
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Carlotta Giorgi
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Simone Patergnani
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
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Zhou X, He YZ, Liu D, Lin CR, Liang D, Huang R, Wang L. An Autophagy-Related Gene Signature can Better Predict Prognosis and Resistance in Diffuse Large B-Cell Lymphoma. Front Genet 2022; 13:862179. [PMID: 35846146 PMCID: PMC9280409 DOI: 10.3389/fgene.2022.862179] [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: 01/25/2022] [Accepted: 05/12/2022] [Indexed: 01/11/2023] Open
Abstract
Background: Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease, and about 30%–40% of patients will develop relapsed/refractory DLBCL. In this study, we aimed to develop a gene signature to predict survival outcomes of DLBCL patients based on the autophagy-related genes (ARGs). Methods: We sequentially used the univariate, least absolute shrinkage and selector operation (LASSO), and multivariate Cox regression analyses to build a gene signature. The Kaplan–Meier curve and the area under the receiver operating characteristic curve (AUC) were performed to estimate the prognostic capability of the gene signature. GSEA analysis, ESTIMATE and ssGSEA algorithms, and one-class logistic regression were performed to analyze differences in pathways, immune response, and tumor stemness between the high- and low-risk groups. Results: Both in the training cohort and validation cohorts, high-risk patients had inferior overall survival compared with low-risk patients. The nomogram consisted of the autophagy-related gene signature, and clinical factors had better discrimination of survival outcomes, and it also had a favorable consistency between the predicted and actual survival. GSEA analysis found that patients in the high-risk group were associated with the activation of doxorubicin resistance, NF-κB, cell cycle, and DNA replication pathways. The results of ESTIMATE, ssGSEA, and mRNAsi showed that the high-risk group exhibited lower immune cell infiltration and immune activation responses and had higher similarity to cancer stem cells. Conclusion: We proposed a novel and reliable autophagy-related gene signature that was capable of predicting the survival and resistance of patients with DLBCL and could guide individualized treatment in future.
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Affiliation(s)
- Xuan Zhou
- Second Clinical Medical College of Southern Medical University, Zhujiang Hospital of Southern Medical University, Guangzhou, China
- Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Ying-Zhi He
- Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Dan Liu
- The First School of Clinical Medicine, Guangdong Medical University, Zhanjiang, China
| | - Chao-Ran Lin
- The First School of Clinical Medicine, Guangdong Medical University, Zhanjiang, China
| | - Dan Liang
- Second Clinical Medical College of Southern Medical University, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Rui Huang
- Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
- *Correspondence: Rui Huang, ; Liang Wang,
| | - Liang Wang
- Department of Hematology, Beijing TongRen Hospital, Capital Medical University, Beijing, China
- *Correspondence: Rui Huang, ; Liang Wang,
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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: 13] [Impact Index Per Article: 4.3] [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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28
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Du L, Wang D, Nagle PW, Groen AAH, Zhang H, Muijs CT, Plukker JTM, Coppes RP. Role of mTOR through Autophagy in Esophageal Cancer Stemness. Cancers (Basel) 2022; 14:cancers14071806. [PMID: 35406578 PMCID: PMC9040713 DOI: 10.3390/cancers14071806] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/27/2022] [Accepted: 03/30/2022] [Indexed: 02/05/2023] Open
Abstract
Esophageal cancer (EC) is a highly aggressive disease with a poor prognosis. Therapy resistance and early recurrences are major obstacles in reaching a better outcome. Esophageal cancer stem-like cells (CSCs) seem tightly related with chemoradiation resistance, initiating new tumors and metastases. Several oncogenic pathways seem to be involved in the regulation of esophageal CSCs and might harbor novel therapeutic targets to eliminate CSCs. Previously, we identified a subpopulation of EC cells that express high levels of CD44 and low levels of CD24 (CD44+/CD24-), show CSC characteristics and reside in hypoxic niches. Here, we aim to clarify the role of the hypoxia-responding mammalian target of the rapamycin (mTOR) pathway in esophageal CSCs. We showed that under a low-oxygen culture condition and nutrient deprivation, the CD44+/CD24- population is enriched. Since both low oxygen and nutrient deprivation may inhibit the mTOR pathway, we next chemically inhibited the mTOR pathway using Torin-1. Torin-1 upregulated SOX2 resulted in an enrichment of the CD44+/CD24- population and increased sphere formation potential. In contrast, stimulation of the mTOR pathway using MHY1485 induced the opposite effects. In addition, Torin-1 increased autophagic activity, while MHY1485 suppressed autophagy. Torin-1-mediated CSCs upregulation was significantly reduced in cells treated with autophagy inhibitor, hydroxychloroquine (HCQ). Finally, a clearly defined CD44+/CD24- CSC population was detected in EC patients-derived organoids (ec-PDOs) and here, MHY1485 also reduced this population. These data suggest that autophagy may play a crucial role in mTOR-mediated CSCs repression. Stimulation of the mTOR pathway might aid in the elimination of putative esophageal CSCs.
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Affiliation(s)
- Liang Du
- Section Molecular Cell Biology, Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.D.); (D.W.); (P.W.N.); (A.A.H.G.)
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands;
- Graduate School, Shantou University Medical College, Shantou 515041, China
| | - Da Wang
- Section Molecular Cell Biology, Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.D.); (D.W.); (P.W.N.); (A.A.H.G.)
- Department of Surgery, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands;
| | - Peter W. Nagle
- Section Molecular Cell Biology, Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.D.); (D.W.); (P.W.N.); (A.A.H.G.)
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands;
- Medical Research Council (MRC) Centre for Reproductive Health, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Andries A. H. Groen
- Section Molecular Cell Biology, Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.D.); (D.W.); (P.W.N.); (A.A.H.G.)
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands;
| | - Hao Zhang
- Department of Pathology, Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou 510632, China;
- Department of General Surgery, First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Christina T. Muijs
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands;
| | - John Th. M. Plukker
- Department of Surgery, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands;
| | - Robert P. Coppes
- Section Molecular Cell Biology, Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.D.); (D.W.); (P.W.N.); (A.A.H.G.)
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands;
- Correspondence:
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A perspective on the role of autophagy in cancer. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166262. [PMID: 34481059 DOI: 10.1016/j.bbadis.2021.166262] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/20/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022]
Abstract
Autophagy refers to a ubiquitous set of catabolic pathways required to achieve proper cellular homeostasis. Aberrant autophagy has been implicated in a multitude of diseases including cancer. In this review, we highlight pioneering and groundbreaking research that centers on delineating the role of autophagy in cancer initiation, proliferation and metastasis. First, we discuss the autophagy-related (ATG) proteins and their respective roles in the de novo formation of autophagosomes and the subsequent delivery of cargo to the lysosome for recycling. Next, we touch upon the history of cancer research that centers upon ATG proteins and regulatory mechanisms that control an appropriate autophagic response and how these are altered in the diseased state. Then, we discuss the various discoveries that led to the idea of autophagy as a double-edged sword when it comes to cancer therapy. This review also briefly narrates how different types of autophagy-selective macroautophagy and chaperone-mediated autophagy, have been linked to different cancers. Overall, these studies build upon a steadfast trajectory that aims to solve the monumentally daunting challenge of finding a cure for many types of cancer by modulating autophagy either through inhibition or induction.
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Cao J, Bhatnagar S, Wang J, Qi X, Prabha S, Panyam J. Cancer stem cells and strategies for targeted drug delivery. Drug Deliv Transl Res 2021; 11:1779-1805. [PMID: 33095384 PMCID: PMC8062588 DOI: 10.1007/s13346-020-00863-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/01/2020] [Indexed: 12/23/2022]
Abstract
Cancer stem cells (CSCs) are a small proportion of cancer cells with high tumorigenic activity, self-renewal ability, and multilineage differentiation potential. Standard anti-tumor therapies including conventional chemotherapy, radiation therapy, and molecularly targeted therapies are not effective against CSCs, and often lead to enrichment of CSCs that can result in tumor relapse. Therefore, it is hypothesized that targeting CSCs is key to increasing the efficacy of cancer therapies. In this review, CSC properties including CSC markers, their role in tumor growth, invasiveness, metastasis, and drug resistance, as well as CSC microenvironment are discussed. Further, CSC-targeted strategies including the use of targeted drug delivery systems are examined.
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Affiliation(s)
- Jin Cao
- School of Pharmacy, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
- College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Shubhmita Bhatnagar
- College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA
- School of Pharmacy, Temple University, Philadelphia, PA, 19140, USA
| | - Jiawei Wang
- College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA
- College of Pharmacy, University of Texas at Austin, Austin, TX, 78712, USA
| | - Xueyong Qi
- School of Pharmacy, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Swayam Prabha
- College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA
- Cancer Research & Molecular Biology and Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Jayanth Panyam
- College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA.
- School of Pharmacy, Temple University, Philadelphia, PA, 19140, USA.
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Mukhopadhyay S, Mahapatra KK, Praharaj PP, Patil S, Bhutia SK. Recent progress of autophagy signaling in tumor microenvironment and its targeting for possible cancer therapeutics. Semin Cancer Biol 2021; 85:196-208. [PMID: 34500075 DOI: 10.1016/j.semcancer.2021.09.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 08/30/2021] [Accepted: 09/03/2021] [Indexed: 02/08/2023]
Abstract
Autophagy, a lysosomal catabolic process, involves degradation of cellular materials, protein aggregate, and dysfunctional organelles to maintain cellular homeostasis. Strikingly, autophagy exhibits a dual-sided role in cancer; on the one hand, it promotes clearance of transformed cells and inhibits tumorigenesis, while cytoprotective autophagy has a role in sustaining cancer. The autophagy signaling in the tumor microenvironment (TME) during cancer growth and therapy is not adequately understood. The review highlights the role of autophagy signaling pathways to support cancer growth and progression in adaptation to the oxidative and hypoxic context of TME. Furthermore, autophagy contributes to regulating the metabolic switch for generating sufficient levels of high-energy metabolites, including amino acids, ketones, glutamine, and free fatty acids for cancer cell survival. Interestingly, autophagy has a critical role in modulating the tumor-associated fibroblast resulting in different cytokines and paracrine signaling mediated angiogenesis and invasion of pre-metastatic niches to secondary tumor sites. Moreover, autophagy promotes immune evasion to inhibit antitumor immunity, and autophagy inhibitors enhance response to immunotherapy with infiltration of immune cells to the TME niche. Furthermore, autophagy in TME maintains and supports the survival of cancer stem cells resulting in chemoresistance and therapy recurrence. Presently, drug repurposing has enabled the use of lysosomal inhibitor-based antimalarial drugs like chloroquine and hydroxychloroquine as clinically available autophagy inhibitors in cancer therapy. We focus on the recent developments of multiple autophagy modulators from pre-clinical trials and the challenges in developing autophagy-based cancer therapy.
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Affiliation(s)
- Subhadip Mukhopadhyay
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India
| | - Kewal Kumar Mahapatra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India
| | - Prakash Priyadarshi Praharaj
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Saudi Arabia
| | - Sujit Kumar Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India.
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Ascenzi F, De Vitis C, Maugeri-Saccà M, Napoli C, Ciliberto G, Mancini R. SCD1, autophagy and cancer: implications for therapy. J Exp Clin Cancer Res 2021; 40:265. [PMID: 34429143 PMCID: PMC8383407 DOI: 10.1186/s13046-021-02067-6] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/09/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Autophagy is an intracellular degradation system that removes unnecessary or dysfunctional components and recycles them for other cellular functions. Over the years, a mutual regulation between lipid metabolism and autophagy has been uncovered. METHODS This is a narrative review discussing the connection between SCD1 and the autophagic process, along with the modality through which this crosstalk can be exploited for therapeutic purposes. RESULTS Fatty acids, depending on the species, can have either activating or inhibitory roles on autophagy. In turn, autophagy regulates the mobilization of fat from cellular deposits, such as lipid droplets, and removes unnecessary lipids to prevent cellular lipotoxicity. This review describes the regulation of autophagy by lipid metabolism in cancer cells, focusing on the role of stearoyl-CoA desaturase 1 (SCD1), the key enzyme involved in the synthesis of monounsaturated fatty acids. SCD1 plays an important role in cancer, promoting cell proliferation and metastasis. The role of autophagy in cancer is more complex since it can act either by protecting against the onset of cancer or by promoting tumor growth. Mounting evidence indicates that autophagy and lipid metabolism are tightly interconnected. CONCLUSION Here, we discuss controversial findings of SCD1 as an autophagy inducer or inhibitor in cancer, highlighting how these activities may result in cancer promotion or inhibition depending upon the degree of cancer heterogeneity and plasticity.
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Affiliation(s)
- Francesca Ascenzi
- Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, "Sapienza" University of Rome, 00161, Rome, Italy
| | - Claudia De Vitis
- Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, "Sapienza" University of Rome, 00161, Rome, Italy
| | - Marcello Maugeri-Saccà
- Division of Medical Oncology 2, IRCCS "Regina Elena" National Cancer Institute, 00144, Rome, Italy
| | - Christian Napoli
- Department of Medical Surgical Sciences and Translational Medicine, "Sapienza" University of Rome, 00189, Rome, Italy
| | - Gennaro Ciliberto
- Scientific Direction, IRCCS "Regina Elena" National Cancer Institute, 00144, Rome, Italy
| | - Rita Mancini
- Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, "Sapienza" University of Rome, 00161, Rome, Italy.
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Mandhair HK, Novak U, Radpour R. Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells. World J Stem Cells 2021; 13:542-567. [PMID: 34249227 PMCID: PMC8246247 DOI: 10.4252/wjsc.v13.i6.542] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/02/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
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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: 42] [Impact Index Per Article: 10.5] [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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Anand K, Niravath P, Patel T, Ensor J, Rodriguez A, Boone T, Wong ST, Chang JC. A Phase II Study of the Efficacy and Safety of Chloroquine in Combination With Taxanes in the Treatment of Patients With Advanced or Metastatic Anthracycline-refractory Breast Cancer. Clin Breast Cancer 2021; 21:199-204. [PMID: 34159901 PMCID: PMC8300878 DOI: 10.1016/j.clbc.2020.09.015] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 09/12/2020] [Accepted: 09/29/2020] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Chemotherapy eliminates most of the cancer cells except those with potential for self-renewal and tumor initiation, called cancer stem cells (CSCs). Chloroquine, through bioinformatics, was found to be a potential agent to target CSCs. We designed a phase II trial to test the efficacy and safety of chloroquine in combination with taxane or taxane-like chemotherapy agents in patients with advanced or metastatic breast cancer who are refractory to anthracycline-based chemotherapy. PATIENTS AND METHODS Female patients ≥ 18 years of age who had received prior anthracycline chemotherapy were enrolled in this study. Chloroquine 250 mg was given daily orally with either docetaxel or paclitaxel or nab-paclitaxel or ixabepilone every 3 weeks. The maximum number of 3-week cycles allowed was 6. The primary efficacy endpoint was the objective response rate (ORR). The secondary efficacy endpoints included progression-free survival (PFS) and safety analysis. RESULTS Thirty-eight patients were enrolled in the study, and 31 patients were evaluated for response. The median age was 54.1 years (range, 31.7-78.1 years). The ORR was 45.16% (95% confidence interval [CI], 29.2%-62.2%), which was higher than the expected ORR of 30% (P = .03). Patients were followed for a median of 25.4 months and experienced a median PFS of 12.4 months (95% CI, 4.9-24.6 months) and a median OS of 25.4 months (95% CI, 13.7-83.5 months). The combination was well-tolerated, with only 13.15% of patients experiencing grade ≥ 3 adverse events. CONCLUSION A combination of chloroquine with taxane or taxane-like chemotherapy was efficacious in patients with locally advanced or metastatic breast cancer with prior anthracycline-based chemotherapy.
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Affiliation(s)
| | | | - Tejal Patel
- Houston Methodist Cancer Center, Houston, TX
| | - Joe Ensor
- Houston Methodist Research Institute, Houston, TX
| | | | | | - Stephen T Wong
- Houston Methodist Cancer Center, Houston, TX; Houston Methodist Research Institute, Houston, TX
| | - Jenny C Chang
- Houston Methodist Cancer Center, Houston, TX; Houston Methodist Research Institute, Houston, TX.
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Brunel A, Bégaud G, Auger C, Durand S, Battu S, Bessette B, Verdier M. Autophagy and Extracellular Vesicles, Connected to rabGTPase Family, Support Aggressiveness in Cancer Stem Cells. Cells 2021; 10:1330. [PMID: 34072080 PMCID: PMC8227744 DOI: 10.3390/cells10061330] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/20/2021] [Accepted: 05/24/2021] [Indexed: 12/22/2022] Open
Abstract
Even though cancers have been widely studied and real advances in therapeutic care have been made in the last few decades, relapses are still frequently observed, often due to therapeutic resistance. Cancer Stem Cells (CSCs) are, in part, responsible for this resistance. They are able to survive harsh conditions such as hypoxia or nutrient deprivation. Autophagy and Extracellular Vesicles (EVs) secretion are cellular processes that help CSC survival. Autophagy is a recycling process and EVs secretion is essential for cell-to-cell communication. Their roles in stemness maintenance have been well described. A common pathway involved in these processes is vesicular trafficking, and subsequently, regulation by Rab GTPases. In this review, we analyze the role played by Rab GTPases in stemness status, either directly or through their regulation of autophagy and EVs secretion.
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Li X, Cao Y, Yu X, Jin F, Li Y. A novel autophagy-related genes prognostic risk model and validation of autophagy-related oncogene VPS35 in breast cancer. Cancer Cell Int 2021; 21:265. [PMID: 34001111 PMCID: PMC8130280 DOI: 10.1186/s12935-021-01970-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 04/30/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Accumulating evidence implies that autophagy plays a critical role in breast cancer development and progression. It is crucial to screen out autophagy-related encoding genes (ARGs) with prognostic value in breast cancer and reveal their biological properties in the aggressiveness of breast cancer. METHODS Univariate and multivariate Cox proportional hazards analyses were used to identify a prognostic risk model of ARGs from The Cancer Genome Atlas (TCGA). Kaplan-Meier analysis, univariate and multivariate Cox regression analyses and receiver operating characteristic (ROC) curve analysis were performed to validate the risk model. Western blot and immunohistochemistry (IHC) were conducted to assess the expression of VPS35 (one of ARGs in risk model). CCK8, Colony formation assay, Transwell migration/invasion assays and autophagy flux assay were used to confirm biological function of VPS35 in breast cancer. RESULTS In this study, the prognostic risk model consisting of six ARGs (VPS35, TRIM21, PRKAB2, RUFY4, MAP1LC3A and LARP1) in breast cancer were identified. The risk model was further verified as a novel independent prognostic factor for breast cancer patients. We also clarified that vacuolar protein sorting-associated protein 35 (VPS35), one of ARGs in the risk model, was upregulated in breast cancer samples and cell lines. VPS35 overexpression was correlated with more aggressive phenotype of breast cancer and indicated worse prognosis in both progression-free survival and overall survival analyses. Meanwhile, VPS35 knockdown inhibited breast cancer cell proliferation, migration and invasion, suggesting that VPS35 promoted the progression of breast cancer. VPS35 silence also influenced autophagy process, indicating that VPS35 was essential for autophagy completion. CONCLUSION Taken together, the six ARGs risk model has a remarkably prognostic value for breast cancer. Among them, VPS35 might exert as a significant oncogenic and prognostic factor for breast cancer and could be a promising autophagy-related therapeutic target in clinical practice.
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Affiliation(s)
- Xiaoying Li
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, 155 Nanjing Road, Shenyang, 110001, China.,Department of Cell Biology, Key Laboratory of Cell Biology, National Health Commission of the PRC, and Key Laboratory of Medical Cell Biology, Ministry of Education of the PRC, China Medical University, No. 77, Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, China
| | - Yu Cao
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, 155 Nanjing Road, Shenyang, 110001, China
| | - Xinmiao Yu
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, 155 Nanjing Road, Shenyang, 110001, China
| | - Feng Jin
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, 155 Nanjing Road, Shenyang, 110001, China
| | - Yang Li
- Department of Cell Biology, Key Laboratory of Cell Biology, National Health Commission of the PRC, and Key Laboratory of Medical Cell Biology, Ministry of Education of the PRC, China Medical University, No. 77, Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, China.
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Gomez-Gutierrez JG, Bhutiani N, McNally MW, Chuong P, Yin W, Jones MA, Zeiderman MR, Grizzle WE, McNally LR. The neutral red assay can be used to evaluate cell viability during autophagy or in an acidic microenvironment in vitro. Biotech Histochem 2021; 96:302-310. [PMID: 32744455 PMCID: PMC7861123 DOI: 10.1080/10520295.2020.1802065] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Harsh conditions within the tumor microenvironment, such as hypoxia and extracellular acidic pH (pHe), inactivate some chemotherapies, which results in limited or no cytotoxicity. Standard MTT, ATPlite and protease assays that are used to determine the potency of newly developed drugs often give erroneous results when applied under hypoxic or acidic conditions. Therefore, development of a cytotoxicity assay that does not yield false positive or false negative results under circumstances of both hypoxia and acidic pHe is needed. We evaluated currently used cell viability assays as well as neutral red staining to assess viability of ovarian and pancreatic cancer cells grown in an acidic pHe microenvironment after treatment with carboplatin, gemcitabine or chloroquine. We validated cell viability using western blotting of pro-caspase-9 and cleaved-caspase-9, and LC3-I and - II. Standard cell viability assays indicated cell viability accurately at pHe 7.4, but was not correlated with induction of apoptosis or autophagy at acidic pHe. By contrast, our modified neutral red assay detected cell viability accurately over a range of pHe as demonstrated by its correlation with induction of apoptosis and autophagy. Neutral red staining is effective for evaluating the effect of chemotherapeutic agents on cell viability under acidic pHe or hypoxic conditions.
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Affiliation(s)
| | - Neal Bhutiani
- Department of Surgery, University of Louisville, Louisville, Kentucky
| | - Molly W McNally
- Department of Surgery, University of Oklahoma, Oklahoma City, Oklahoma
| | - Phillip Chuong
- Department of Surgery, University of Louisville, Louisville, Kentucky
| | - Wenyuan Yin
- Department of Surgery, University of Louisville, Louisville, Kentucky
| | | | | | - William E Grizzle
- Department of Pathology, University of Alabama Birmingham, Birmingham, Alabama
| | - Lacey R. McNally
- Department of Surgery, University of Oklahoma, Oklahoma City, Oklahoma
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Interplay between Metabolism Reprogramming and Epithelial-to-Mesenchymal Transition in Cancer Stem Cells. Cancers (Basel) 2021; 13:cancers13081973. [PMID: 33923958 PMCID: PMC8072988 DOI: 10.3390/cancers13081973] [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: 03/25/2021] [Revised: 04/14/2021] [Accepted: 04/15/2021] [Indexed: 01/10/2023] Open
Abstract
Simple Summary Tumor cells display important plasticity potential. Notably, tumor cells have the ability to change toward immature cells called cancer stem cells under the influence of the tumor environment. Importantly, cancer stem cells are a small subset of relatively quiescent cells that, unlike rapidly dividing differentiated tumor cells, escape standard chemotherapies, causing relapse or recurrence of cancer. Interestingly, these cells adopt a specific metabolism. Most often, they mainly rely on glucose uptake and metabolism to sustain their energy needs. This metabolic reprogramming is set off by environmental factors such as pro-inflammatory signals or catecholamine hormones (epinephrine, norepinephrine). A better understanding of this process could provide opportunities to kill cancer stem cells. Indeed, it would become possible to develop drugs that act specifically on metabolic pathways used by these cells. These new drugs could be used to strengthen the effects of current chemotherapies and overcome cancers with poor prognoses. Abstract Tumor cells display important plasticity potential, which contributes to intratumoral heterogeneity. Notably, tumor cells have the ability to retrodifferentiate toward immature states under the influence of their microenvironment. Importantly, this phenotypical conversion is paralleled by a metabolic rewiring, and according to the metabostemness theory, metabolic reprogramming represents the first step of epithelial-to-mesenchymal transition (EMT) and acquisition of stemness features. Most cancer stem cells (CSC) adopt a glycolytic phenotype even though cells retain functional mitochondria. Such adaptation is suggested to reduce the production of reactive oxygen species (ROS), protecting CSC from detrimental effects of ROS. CSC may also rely on glutaminolysis or fatty acid metabolism to sustain their energy needs. Besides pro-inflammatory cytokines that are well-known to initiate the retrodifferentiation process, the release of catecholamines in the microenvironment of the tumor can modulate both EMT and metabolic changes in cancer cells through the activation of EMT transcription factors (ZEB1, Snail, or Slug (SNAI2)). Importantly, the acquisition of stem cell properties favors the resistance to standard care chemotherapies. Hence, a better understanding of this process could pave the way for the development of therapies targeting CSC metabolism, providing new strategies to eradicate the whole tumor mass in cancers with unmet needs.
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Talukdar S, Das SK, Emdad L, Fisher PB. Autophagy and senescence: Insights from normal and cancer stem cells. Adv Cancer Res 2021; 150:147-208. [PMID: 33858596 DOI: 10.1016/bs.acr.2021.01.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Autophagy is a fundamental cellular process, which allows cells to adapt to metabolic stress through the degradation and recycling of intracellular components to generate macromolecular precursors and produce energy. Autophagy is also critical in maintaining cellular/tissue homeostasis, as well preserving immunity and preventing human disease. Deregulation of autophagic processes is associated with cancer, neurodegeneration, muscle and heart disease, infectious diseases and aging. Research on a variety of stem cell types establish that autophagy plays critical roles in normal and cancer stem cell quiescence, activation, differentiation, and self-renewal. Considering its critical function in regulating the metabolic state of stem cells, autophagy plays a dual role in the regulation of normal and cancer stem cell senescence, and cellular responses to various therapeutic strategies. The relationships between autophagy, senescence, dormancy and apoptosis frequently focus on responses to various forms of stress. These are interrelated processes that profoundly affect normal and abnormal human physiology that require further elucidation in cancer stem cells. This review provides a current perspective on autophagy and senescence in both normal and cancer stem cells.
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Affiliation(s)
- Sarmistha Talukdar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
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Jahangiri L, Ishola T, Pucci P, Trigg RM, Pereira J, Williams JA, Cavanagh ML, Gkoutos GV, Tsaprouni L, Turner SD. The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells. Cancers (Basel) 2021; 13:cancers13061239. [PMID: 33799834 PMCID: PMC7998932 DOI: 10.3390/cancers13061239] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/06/2021] [Accepted: 03/08/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Cancer stem cells (CSCs) represent a distinct cancer subpopulation that can influence the tumour microenvironment, in addition to cancer progression and relapse. A multitude of factors including CSC properties, long noncoding RNAs (lncRNAs), and autophagy play pivotal roles in maintaining CSCs. We discuss the methods of detection of CSCs and how our knowledge of regulatory and cellular processes, and their interaction with the microenvironment, may lead to more effective targeting of these cells. Autophagy and lncRNAs can regulate several cellular functions, thereby promoting stemness factors and CSC properties, hence understanding this triangle and its associated signalling networks can lead to enhanced therapy response, while paving the way for the development of novel therapeutic approaches. Abstract Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.
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Affiliation(s)
- Leila Jahangiri
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
- Correspondence: (L.J.); (G.V.G.)
| | - Tala Ishola
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
| | - Perla Pucci
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
| | - Ricky M. Trigg
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
- Department of Functional Genomics, GlaxoSmithKline, Stevenage SG1 2NY, UK
| | - Joao Pereira
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA;
| | - John A. Williams
- Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK;
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2SY, UK
| | - Megan L. Cavanagh
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
| | - Georgios V. Gkoutos
- Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK;
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2SY, UK
- Mammalian Genetics Unit, Medical Research Council Harwell Institute, Oxfordshire OX110RD, UK
- MRC Health Data Research Midlands, University of Birmingham, Birmingham B15 2TT, UK
- NIHR Experimental Cancer Medicine Centre, Birmingham B15 2TT, UK
- NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham B15 2TT, UK
- NIHR Biomedical Research Centre, Birmingham B15 2TT, UK
- Correspondence: (L.J.); (G.V.G.)
| | - Loukia Tsaprouni
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
| | - Suzanne D. Turner
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
- Central European Institute of Technology (CEITEC), Masaryk University, 625 00 Brno, Czech Republic
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The CD44high Subpopulation of Multifraction Irradiation-Surviving NSCLC Cells Exhibits Partial EMT-Program Activation and DNA Damage Response Depending on Their p53 Status. Int J Mol Sci 2021; 22:ijms22052369. [PMID: 33673439 PMCID: PMC7956695 DOI: 10.3390/ijms22052369] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/15/2021] [Accepted: 02/24/2021] [Indexed: 02/07/2023] Open
Abstract
Ionizing radiation (IR) is used for patients diagnosed with unresectable non-small cell lung cancer (NSCLC). However, radiotherapy remains largely palliative due to the survival of specific cell subpopulations. In the present study, the sublines of NSCLC cells, A549IR (p53wt) and H1299IR (p53null) survived multifraction X-ray radiation exposure (MFR) at a total dose of 60 Gy were investigated three weeks after the MFR course. We compared radiosensitivity (colony formation), expression of epithelial-mesenchymal transition (EMT) markers, migration activity, autophagy, and HR-dependent DNA double-strand break (DSB) repair in the bulk and entire CD44high/CD166high CSC-like populations of both parental and MFR survived NSCLC cells. We demonstrated that the p53 status affected: the pattern of expression of N-cadherin, E-cadherin, Vimentin, witnessing the appearance of EMT-like phenotype of MFR-surviving sublines; 1D confined migratory behavior (wound healing); the capability of an irradiated cell to continue to divide and form a colony of NSCLC cells before and after MFR; influencing the CD44/CD166 expression level in MFR-surviving NSCLC cells after additional single irradiation. Our data further emphasize the impact of p53 status on the decay of γH2AX foci and the associated efficacy of the DSB repair in NSCLC cells survived after MFR. We revealed that Rad51 protein might play a principal role in MFR-surviving of p53 null NSCLC cells promoting DNA DSB repair by homologous recombination (HR) pathway. The proportion of Rad51 + cells elevated in CD44high/CD166high population in MFR-surviving p53wt and p53null sublines and their parental cells. The p53wt ensures DNA-PK-mediated DSB repair for both parental and MFR-surviving cells irrespectively of a subsequent additional single irradiation. Whereas in the absence of p53, a dose-dependent increase of DNA-PK-mediated non-homologous end joining (NHEJ) occurred as an early post-irradiation response is more intensive in the CSC-like population MFR-surviving H1299IR, compared to their parental H1299 cells. Our study strictly observed a significantly higher content of LC3 + cells in the CD44high/CD166high populations of p53wt MFR-surviving cells, which enriched the CSC-like cells in contrast to their p53null counterparts. The additional 2 Gy and 5 Gy X-ray exposure leads to the dose-dependent increase in the proportion of LC3 + cells in CD44high/CD166high population of both parental p53wt and p53null, but not MFR-surviving NSCLC sublines. Our data indicated that autophagy is not necessarily associated with CSC-like cells’ radiosensitivity, emphasizing that careful assessment of other milestone processes (such as senescence and autophagy-p53-Zeb1 axis) of primary radiation responses may provide new potential targets modulated for therapeutic benefit through radiosensitizing cancer cells while rescuing normal tissue. Our findings also shed light on the intricate crosstalk between autophagy and the p53-related EMT, by which MFR-surviving cells might obtain an invasive phenotype and metastatic potential.
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Role of Hypoxia-Mediated Autophagy in Tumor Cell Death and Survival. Cancers (Basel) 2021; 13:cancers13030533. [PMID: 33573362 PMCID: PMC7866864 DOI: 10.3390/cancers13030533] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 12/14/2022] Open
Abstract
Programmed cell death or type I apoptosis has been extensively studied and its contribution to the pathogenesis of disease is well established. However, autophagy functions together with apoptosis to determine the overall fate of the cell. The cross talk between this active self-destruction process and apoptosis is quite complex and contradictory as well, but it is unquestionably decisive for cell survival or cell death. Autophagy can promote tumor suppression but also tumor growth by inducing cancer-cell development and proliferation. In this review, we will discuss how autophagy reprograms tumor cells in the context of tumor hypoxic stress. We will illustrate how autophagy acts as both a suppressor and a driver of tumorigenesis through tuning survival in a context dependent manner. We also shed light on the relationship between autophagy and immune response in this complex regulation. A better understanding of the autophagy mechanisms and pathways will undoubtedly ameliorate the design of therapeutics aimed at targeting autophagy for future cancer immunotherapies.
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Abstract
Autophagy is deregulated in many cancers and represents an attractive target for therapeutic intervention. However, the precise contributions of autophagy to metastatic progression, the principle cause of cancer-related mortality, is only now being uncovered. While autophagy promotes primary tumor growth, metabolic adaptation and resistance to therapy, recent studies have unexpectedly revealed that autophagy suppresses the proliferative outgrowth of disseminated tumor cells into overt and lethal macrometastases. These studies suggest autophagy plays unexpected and complex roles in the initiation and progression of metastases, which will undoubtedly impact therapeutic approaches for cancer treatment. Here, we discuss the intricacies of autophagy in metastatic progression, highlighting and integrating the pleiotropic roles of autophagy on diverse cell biological processes involved in metastasis.
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Affiliation(s)
- Timothy Marsh
- Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143 USA
| | - Bhairavi Tolani
- Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94115 USA
| | - Jayanta Debnath
- Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143 USA
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Autophagy augments the self-renewal of lung cancer stem cells by the degradation of ubiquitinated p53. Cell Death Dis 2021; 12:98. [PMID: 33468994 PMCID: PMC7815724 DOI: 10.1038/s41419-021-03392-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 12/28/2020] [Accepted: 12/30/2020] [Indexed: 12/12/2022]
Abstract
It has been postulated that cancer stem cells (CSCs) are involved in all aspects of human cancer, although the mechanisms governing the regulation of CSC self-renewal in the cancer state remain poorly defined. In the literature, both the pro- and anti-oncogenic activities of autophagy have been demonstrated and are context-dependent. Mounting evidence has shown augmentation of CSC stemness by autophagy, yet mechanistic characterization and understanding are lacking. In the present study, by generating stable human lung CSC cell lines with the wild-type TP53 (A549), as well as cell lines in which TP53 was deleted (H1229), we show, for the first time, that autophagy augments the stemness of lung CSCs by degrading ubiquitinated p53. Furthermore, Zeb1 is required for TP53 regulation of CSC self-renewal. Moreover, TCGA data mining and analysis show that Atg5 and Zeb1 are poor prognostic markers of lung cancer. In summary, this study has elucidated a new CSC-based mechanism underlying the oncogenic activity of autophagy and the tumor suppressor activity of p53 in cancer, i.e., CSCs can exploit the autophagy-p53-Zeb1 axis for self-renewal, oncogenesis, and progression.
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Maiti A, Hait NC. Autophagy-mediated tumor cell survival and progression of breast cancer metastasis to the brain. J Cancer 2021; 12:954-964. [PMID: 33442395 PMCID: PMC7797661 DOI: 10.7150/jca.50137] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 10/07/2020] [Indexed: 02/07/2023] Open
Abstract
Brain metastases represent a substantial amount of morbidity and mortality in breast cancer (BC). Metastatic breast tumor cells committed to brain metastases are unique because they escape immune surveillance, can penetrate the blood-brain barrier, and also adapt to the brain tissue microenvironment (TME) for colonization and outgrowth. In addition, dynamic intracellular interactions between metastatic cancer cells and neighboring astrocytes in the brain are thought to play essential roles in brain tumor progression. A better understanding of the above mechanisms will lead to developing more effective therapies for brain metastases. Growing literature suggests autophagy, a conserved lysosomal degradation pathway involved in cellular homeostasis under stressful conditions, plays essential roles in breast tumor metastatic transformation and brain metastases. Cancer cells must adapt under various microenvironmental stresses, such as hypoxia, and nutrient (glucose) deprivation, in order to survive and progress. Clinical studies reveal that tumoral expression of autophagy-related proteins is higher in brain metastasis compared to primary breast tumors. In this review, we outline the molecular mechanisms underlying autophagy-mediated BC cell survival and metastasis to the brain.
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Affiliation(s)
- Aparna Maiti
- Division of Breast Surgery and Department of Surgical Oncology, Department of Molecular & Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, 14263, USA
| | - Nitai C. Hait
- Division of Breast Surgery and Department of Surgical Oncology, Department of Molecular & Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, 14263, USA
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Chen Q, Zhong L, Zhou C, Feng Y, Liu QX, Zhou D, Lu X, Du GS, Jian D, Luo H, Wang D, Zheng H, Qiu Y. Knockdown of Parkinson's disease-related gene ATP13A2 reduces tumorigenesis via blocking autophagic flux in colon cancer. Cell Biosci 2020; 10:144. [PMID: 33308286 PMCID: PMC7731751 DOI: 10.1186/s13578-020-00506-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 11/27/2020] [Indexed: 02/07/2023] Open
Abstract
Background Accumulating evidence shows that Parkinson’s disease is negatively associated with colon cancer risk, indicating that Parkinson’s disease family proteins may be involved in the initiation of colon cancer. Here, we aimed to identify a Parkinson’s disease-related gene involved in colon cancer, elucidate the underlying mechanisms, and test whether it can be used as a target for cancer therapy. Methods We first screened colon cancer and normal tissues for differential expression of Parkinson’s disease-associated genes and identified ATP13A2, which encodes cation-transporting ATPase 13A2, as a putative marker for colon cancer. We next correlated ATP13A2 expression with colon cancer prognosis. We performed a series of ATP13A2 knockdown and overexpression studies in vitro to identify the contribution of ATP13A2 in the stemness and invasive capacity of colon cancer cells. Additionally, autophagy flux assay were determined to explore the mechanism of ATP13A2 induced stemness. Finally, we knocked down ATP13A2 in mice using siRNA to determine whether it can be used as target for colon cancer treatment. Results Colon cancer patients with high ATP13A2 expression exhibit shorter overall survival than those with low ATP13A2. Functionally, ATP13A2 acts as a novel stimulator of stem-like traits. Furthermore, knockdown of ATP13A2 in HCT116 resulted in decreased levels of cellular autophagy. Additionally, bafilomycin A1, an autophagy inhibitor, reversed the ATP13A2-induced stemness of colon cancer cells. Lastly treatment with ATP13A2 siRNA reduced the volume of colon cancer xenografts in mice. Conclusions The PD-associated gene ATP13A2 is involved in colon cancer stemness through regulation of autophagy. Furthermore, ATP13A2 is a novel prognostic biomarker for colon cancer and is a potential target for colon cancer therapy.
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Affiliation(s)
- Qian Chen
- Cancer Center of Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China.,State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Li Zhong
- Cancer Center of Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Chao Zhou
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Yan Feng
- Cancer Center of Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Quan-Xing Liu
- Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Dong Zhou
- Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Xiao Lu
- Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Guang-Sheng Du
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Dan Jian
- Cancer Center of Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Hao Luo
- Cancer Center of Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Dong Wang
- Cancer Center of Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Hong Zheng
- Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China.
| | - Yuan Qiu
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China. .,State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400037, China.
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Camuzard O, Trojani MC, Santucci-Darmanin S, Pagnotta S, Breuil V, Carle GF, Pierrefite-Carle V. Autophagy in Osteosarcoma Cancer Stem Cells Is Critical Process which Can Be Targeted by the Antipsychotic Drug Thioridazine. Cancers (Basel) 2020; 12:cancers12123675. [PMID: 33297525 PMCID: PMC7762415 DOI: 10.3390/cancers12123675] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Cancer stem cells (CSCs) represent a minor population of cancer cells with stem cell-like properties and appear as a crucial target in oncology as they are the origin of relapses and resistance to current treatments. Autophagy, which allows the degradation and recycling of cellular components for survival purposes, has been shown to be upregulated in some CSCs, participating in the resistance of these cells. The aim of our study was to analyze the autophagy level and the consequences of targeting this process in osteosarcoma CSCs. Our results indicate that autophagy is a critical process in osteosarcoma CSCs and that targeting this pathway allows to switch their fate from survival to death. Abstract Cancer stem cells (CSCs) represent a minor population of cancer cells with stem cell-like properties which are able to fuel tumor growth and resist conventional treatments. Autophagy has been described to be upregulated in some CSCs and to play a crucial role by maintaining stem features and promoting resistance to both hostile microenvironments and treatments. Osteosarcoma (OS) is an aggressive bone cancer which mainly affects children and adolescents and autophagy in OS CSCs has been poorly studied. However, this is a very interesting case because autophagy is often deregulated in this cancer. In the present work, we used two OS cell lines showing different autophagy capacities to isolate CSC-enriched populations and to analyze the autophagy in basal and nutrient-deprived conditions. Our results indicate that autophagy is more efficient in CSCs populations compared to the parental cell lines, suggesting that autophagy is a critical process in OS CSCs. We also showed that the antipsychotic drug thioridazine is able to stimulate, and then impair autophagy in both CSC-enriched populations, leading to autosis, a cell death mediated by the Na+/K+ ATPase pump and triggered by dysregulated accumulation of autophagosomes. Taken together, our results indicate that autophagy is very active in OS CSCs and that targeting this pathway to switch their fate from survival to death could provide a novel strategy to eradicate these cells in osteosarcoma.
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Affiliation(s)
- Olivier Camuzard
- Faculté de Médecine Nice, Université Côte d’Azur, UMR E-4320 TIRO-MATOs CEA/DRF/Institut Joliot, CEDEX 2, 06107 Nice, France; (O.C.); (M.-C.T.); (S.S.-D.); (V.B.); (G.F.C.)
- Service de Chirurgie Réparatrice et de la Main, CHU de Nice, 06001 Nice, France
| | - Marie-Charlotte Trojani
- Faculté de Médecine Nice, Université Côte d’Azur, UMR E-4320 TIRO-MATOs CEA/DRF/Institut Joliot, CEDEX 2, 06107 Nice, France; (O.C.); (M.-C.T.); (S.S.-D.); (V.B.); (G.F.C.)
- Service de Rhumatologie, CHU de Nice, 06001 Nice, France
| | - Sabine Santucci-Darmanin
- Faculté de Médecine Nice, Université Côte d’Azur, UMR E-4320 TIRO-MATOs CEA/DRF/Institut Joliot, CEDEX 2, 06107 Nice, France; (O.C.); (M.-C.T.); (S.S.-D.); (V.B.); (G.F.C.)
| | - Sophie Pagnotta
- Centre Commun de Microscopie Appliquée, Université Côte d’Azur, 06107 Nice, France;
| | - Véronique Breuil
- Faculté de Médecine Nice, Université Côte d’Azur, UMR E-4320 TIRO-MATOs CEA/DRF/Institut Joliot, CEDEX 2, 06107 Nice, France; (O.C.); (M.-C.T.); (S.S.-D.); (V.B.); (G.F.C.)
- Service de Rhumatologie, CHU de Nice, 06001 Nice, France
| | - Georges F. Carle
- Faculté de Médecine Nice, Université Côte d’Azur, UMR E-4320 TIRO-MATOs CEA/DRF/Institut Joliot, CEDEX 2, 06107 Nice, France; (O.C.); (M.-C.T.); (S.S.-D.); (V.B.); (G.F.C.)
| | - Valérie Pierrefite-Carle
- Faculté de Médecine Nice, Université Côte d’Azur, UMR E-4320 TIRO-MATOs CEA/DRF/Institut Joliot, CEDEX 2, 06107 Nice, France; (O.C.); (M.-C.T.); (S.S.-D.); (V.B.); (G.F.C.)
- Correspondence: ; Tel.: +33-4-93-37-77-06; Fax: +33-4-93-37-77-17
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Jin KT, Lu ZB, Lv JQ, Zhang JG. The role of long non-coding RNAs in mediating chemoresistance by modulating autophagy in cancer. RNA Biol 2020; 17:1727-1740. [PMID: 32129701 PMCID: PMC7714480 DOI: 10.1080/15476286.2020.1737787] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 02/19/2020] [Accepted: 02/21/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer is a complex process in which protein-coding and non-coding genes play essential roles. Long noncoding RNAs (lncRNAs), as a subclass of noncoding genes, are implicated in various cancer processes including growth, proliferation, metastasis, and angiogenesis. Due to presence in body fluids such as blood and urine, lncRNAs have become novel biomarkers in cancer detection, diagnosis, progression, and therapy response. Remarkably, increasing evidence has verified that lncRNAs play essential roles in chemoresistance by targeting different signalling pathways. Autophagy, a highly conserved process in response to environmental stresses such as starvation and hypoxia, plays a paradoxical role in inducing resistance or sensitivity to chemotherapy agents. In this regard, we reviewed chemoresistance, the role of lncRNAs in cancer, and the role of lncRNAs in chemoresistance by modulating autophagy.
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Affiliation(s)
- Ke-Tao Jin
- Department of Colorectal Surgery, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, Zhejiang Province, P.R. China
| | - Ze-Bei Lu
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou, Zhejiang Province, P.R. China
| | - Jie-Qing Lv
- Department of Colorectal Surgery, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, Zhejiang Province, P.R. China
| | - Jun-Gang Zhang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou, Zhejiang Province, P.R. China
- Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou, Zhejiang Province, P.R. China
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Silva VR, Neves SP, Santos LDS, Dias RB, Bezerra DP. Challenges and Therapeutic Opportunities of Autophagy in Cancer Therapy. Cancers (Basel) 2020; 12:cancers12113461. [PMID: 33233671 PMCID: PMC7699739 DOI: 10.3390/cancers12113461] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/14/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Autophagy is a physiological process characterized by the degradation of the cell components through lysosomes due to stimuli/stress. In this study, we review the challenges and therapeutic opportunities that autophagy presents in the treatment of cancer. We discussed the results of several studies that evaluated autophagy as a therapeutic strategy in cancer, both through the modulation of therapeutic resistance and the death of cancer cells. Moreover, we discussed the role of autophagy in the biology of cancer stem cells and the inhibition of this process as a strategy to overcome resistance and progression of cancer stem cells. Abstract Autophagy is a physiological cellular process that is crucial for development and can occurs in response to nutrient deprivation or metabolic disorders. Interestingly, autophagy plays a dual role in cancer cells—while in some situations, it has a cytoprotective effect that causes chemotherapy resistance, in others, it has a cytotoxic effect in which some compounds induce autophagy-mediated cell death. In this review, we summarize strategies aimed at autophagy for the treatment of cancer, including studies of drugs that can modulate autophagy-mediated resistance, and/or drugs that cause autophagy-mediated cancer cell death. In addition, the role of autophagy in the biology of cancer stem cells has also been discussed.
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