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Horie T, Kuwano A, Sakamoto T, Nakamura Y, Yamaguchi K, Tanida I, Osawa S, Yasumoto K, Ishigaki Y. In silico-based analysis and in vitro experiments identify SIGMAR1 as a potential marker of putative lung cancer stem cells. Discov Oncol 2025; 16:620. [PMID: 40285994 PMCID: PMC12033142 DOI: 10.1007/s12672-025-02394-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 04/15/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Lung cancer is the leading cause of cancer-related mortality worldwide; however, despite the development and clinical application of various drugs, the prognosis remains poor. One reason for this is the high rate of recurrence and metastasis. The cancer stem cell (CSC) theory has been proposed to explain their root cause, and removal of CSCs is necessary to cure cancer completely; however, detailed profiles of lung CSCs have not been clarified. Here, we used single-cell RNA sequencing (scRNA-seq) data to identify novel markers for lung CSCs and validated their expression and function in vitro. METHODS A549-derived tumorspheres were used as a model for lung CSCs. To identify genes upregulated in CSC-like cells, we reanalyzed two publicly available scRNA-seq datasets from human lung cancer tissues. Additionally, trajectory analysis was performed to examine changes in candidate gene expression during CSC differentiation. The role of these candidate genes in CSC regulation was further investigated through functional assays. RESULTS Tumorspheres exhibited increased expression of well-established CSC markers. scRNA-seq analysis suggested that SIGMAR1 expression was significantly upregulated in CSC-like cells and decreased with differentiation. Furthermore, siRNA-mediated SIGMAR1 knockdown suppressed tumorsphere self-renewal capacity and reduced CSC marker expression. CONCLUSIONS We propose that SIGMAR1 serves as a potential functional marker of CSCs and plays a crucial role in regulating self-renewal capacity. Targeting SIGMAR1 may provide a novel therapeutic strategy for preventing metastasis and recurrence-major clinical challenges in lung cancer treatment. Future studies should investigate the underlying mechanisms by which SIGMAR1 modulates CSC properties.
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Affiliation(s)
- Tetsuhiro Horie
- Medical Research Institute, Kanazawa Medical University, Kahoku, Ishikawa, 920-0293, Japan
- Department of Pharmacy, Kanazawa Medical University Hospital, Kahoku, Ishikawa, 920-0293, Japan
| | - Ayane Kuwano
- Genome Biotechnology Laboratory, Kanazawa Institute of Technology, Hakusan, Ishikawa, 924-0838, Japan
| | - Takuya Sakamoto
- Medical Research Institute, Kanazawa Medical University, Kahoku, Ishikawa, 920-0293, Japan
- Department of Pharmacy, Kanazawa Medical University Hospital, Kahoku, Ishikawa, 920-0293, Japan
| | - Yuka Nakamura
- Medical Research Institute, Kanazawa Medical University, Kahoku, Ishikawa, 920-0293, Japan
| | - Kayoko Yamaguchi
- Medical Research Institute, Kanazawa Medical University, Kahoku, Ishikawa, 920-0293, Japan
- Department of Pharmacy, Kanazawa Medical University Hospital, Kahoku, Ishikawa, 920-0293, Japan
| | - Ikuhiro Tanida
- Genome Biotechnology Laboratory, Kanazawa Institute of Technology, Hakusan, Ishikawa, 924-0838, Japan
| | - Satoshi Osawa
- Genome Biotechnology Laboratory, Kanazawa Institute of Technology, Hakusan, Ishikawa, 924-0838, Japan
| | - Kazuo Yasumoto
- Department of Medical Oncology, Kanazawa Medical University, Kahoku, Ishikawa, 920-0293, Japan
| | - Yasuhito Ishigaki
- Medical Research Institute, Kanazawa Medical University, Kahoku, Ishikawa, 920-0293, Japan.
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Lei X, Zheng Y, Su W. RNA-binding proteins and autophagy in lung cancer: mechanistic insights and therapeutic perspectives. Discov Oncol 2025; 16:599. [PMID: 40272614 PMCID: PMC12022210 DOI: 10.1007/s12672-025-02413-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 04/16/2025] [Indexed: 04/27/2025] Open
Abstract
BACKGROUND Lung cancer remains a leading cause of cancer-related mortality worldwide. Its progression is intricately associated with the dynamic regulation of autophagy and RNA-binding proteins (RBPs), which play crucial roles in mRNA stability, alternative splicing, and cellular stress responses. OBJECTIVES This review aims to systematically analyze the mechanisms through which RBPs and autophagy contribute to lung cancer progression and explore potential therapeutic strategies targeting these pathways. METHODS We reviewed recent studies on the molecular mechanisms by which RBPs regulate tumor proliferation, metabolic adaptation, and their interaction with autophagy. The review also examines the dual roles of autophagy in lung cancer, highlighting its context-dependent effects on cell survival and death. RESULTS The interactions and regulatory networks between RBPs and autophagy involve multiple levels of regulation. RBPs can directly influence autophagy processes and act as microRNA (miRNA) sponges to regulate mRNA stability. The modulation of RBPs affects the expression of autophagy-related genes (ATGs) and autophagosome formation. Additionally, RBPs participate in complex regulatory interactions with non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and other proteins. CONCLUSIONS This review proposes innovative therapeutic strategies that combine RBP-targeting approaches (e.g., small molecule inhibitors, CRISPR gene editing) with autophagy modulators (e.g., mTOR inhibitors, chloroquine) to enhance treatment efficacy. Nanoparticle drug delivery systems and epigenetic regulation offer further opportunities for targeted interventions. This review lays a theoretical foundation for advancing lung cancer research and provides novel insights into synergistic therapies that target both RBPs and autophagy to improve treatment outcomes for lung cancer.
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Affiliation(s)
- Xiao Lei
- Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China
- Zhanjiang Key Laboratory of Tumor Microenvironment and Organoid Research, Zhanjiang, 524001, China
- Department of Guangdong Medical University, Zhanjiang, 524023, China
| | - Yuexin Zheng
- Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China
- Zhanjiang Key Laboratory of Tumor Microenvironment and Organoid Research, Zhanjiang, 524001, China
- Department of Guangdong Medical University, Zhanjiang, 524023, China
| | - Wenmei Su
- Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China.
- Zhanjiang Key Laboratory of Tumor Microenvironment and Organoid Research, Zhanjiang, 524001, China.
- Department of Guangdong Medical University, Zhanjiang, 524023, China.
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Yu J, Sun W, Zhao X, Chen Y. The therapeutic potential of RNA m(6)A in lung cancer. Cell Commun Signal 2024; 22:617. [PMID: 39736743 DOI: 10.1186/s12964-024-01980-5] [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: 07/05/2024] [Accepted: 12/04/2024] [Indexed: 01/01/2025] Open
Abstract
Lung cancer (LC) is a highly malignant and metastatic form of cancer. The global incidence of and mortality from LC is steadily increasing; the mean 5-year overall survival (OS) rate for LC is less than 20%. This frustrating situation may be attributed to the fact that the pathogenesis of LC remains poorly understood and there is still no cure for mid to advanced LC. Methylation at the N6-position of adenosine (N6mA) of RNA (m(6)A) is widely present in human tissues and organs, and has been found to be necessary for cell development and maintenance of homeostasis. However, numerous basic and clinical studies have demonstrated that RNA m(6)A is deregulated in many human malignancies including LC. This can drive LC malignant characteristics such as proliferation, stemness, invasion, epithelial-mesenchymal transition (EMT), metastasis, and therapeutic resistance. Intriguingly, an increasing number of studies have also shown that eliminating RNA m(6)A dysfunction can exert significant anti-cancer effects on LC such as suppression of cell proliferation and viability, induction of cell death, and reversal of treatment insensitivity. The current review comprehensively discusses the therapeutic potential of RNA m(6)A and its underlying molecular mechanisms in LC, providing useful information for the development of novel LC treatment strategies.
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Affiliation(s)
- Jingran Yu
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, No. 39 Huaxiang Road, Shenyang , Liaoning, 110022, China
| | - Wei Sun
- Department of Radiology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang, 110004, China
| | - Xiangxuan Zhao
- Center for Innovative Engineering Technology in Traditional Chinese Medicine, Liaoning University of Traditional Chinese Medicine, No.79 Chongshandong Road, Shenyang, 110847, China.
- Health Sciences Institute, China Medical University, Puhe Road, Shenyang North New Area, Shenyang, 110022, China.
| | - Yingying Chen
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, No. 39 Huaxiang Road, Shenyang , Liaoning, 110022, China.
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Li X, Ding S, Zhang P, Yan J, Yu X, Wang X, Zhan H, Wang Z. Revealing the impact of autophagy-related genes in rheumatoid arthritis: Insights from bioinformatics. Heliyon 2024; 10:e29849. [PMID: 38699021 PMCID: PMC11064156 DOI: 10.1016/j.heliyon.2024.e29849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 04/16/2024] [Accepted: 04/16/2024] [Indexed: 05/05/2024] Open
Abstract
Background Rheumatoid arthritis is a systemic inflammatory autoimmune disease that severely impacts physical and mental health. Autophagy is a cellular process involving the degradation of cellular components in lysosomes. However, from a bioinformatics perspective, autophagy-related genes have not been comprehensively elucidated in rheumatoid arthritis. Methods In this study, we performed differential analysis of autophagy-related genes in rheumatoid arthritis patients using the GSE93272 dataset from the Gene Expression Omnibus database. Marker genes were screened by least absolute shrinkage and selection operator. Based on marker genes, we used unsupervised cluster analysis to elaborate different autophagy clusters, and further identified modules strongly associated with rheumatoid arthritis by weighted gene co-expression network analysis. In addition, we constructed four machine learning models, random forest model, support vector machine model, generalized linear model and extreme gradient boosting based on marker genes, and based on the optimal machine learning model, a nomogram model was constructed for distinguishing between normal individuals and rheumatoid arthritis patients. Finally, five external independent rheumatoid arthritis datasets were used for the validation of our results. Results The results showed that autophagy-related genes had significant expression differences between normal individuals and osteoarthritis patients. Through least absolute shrinkage and selection operator screening, we identified 31 marker genes and found that they exhibited significant synergistic or antagonistic effects in rheumatoid arthritis, and immune cell infiltration analysis revealed significant changes in immune cell abundance. Subsequently, we elaborated different autophagy clusters (cluster 1 and cluster 2) using unsupervised cluster analysis. Next, further by weighted gene co-expression network analysis, we identified a brown module strongly associated with rheumatoid arthritis. In addition, we constructed a nomogram model for five marker genes (CDKN2A, TP53, ATG16L2, FKBP1A, and GABARAPL1) based on a generalized linear model (area under the curve = 1.000), and the predictive efficiency and accuracy of this nomogram model were demonstrated in the calibration curves, the decision curves and the five external independent datasets were validated. Conclusion This study identified marker autophagy-related genes in rheumatoid arthritis and analyzed their impact on the disease, providing new perspectives for understanding the role of autophagy-related genes in rheumatoid arthritis and providing new directions for its individualized treatment.
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Affiliation(s)
- Xin Li
- Traumatology Hand Surgery Department, Haicheng Orthopedic Hospital, Haicheng, China
| | - Shuang Ding
- Department of Orthopedics, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | | | - Jing Yan
- Changchun University of Chinese Medicine, Changchun, China
| | - Xingxing Yu
- Changchun University of Chinese Medicine, Changchun, China
| | - Xukai Wang
- Department of Orthopedics, The Affiliated Hospital of Changchun University of Chinese Medicine, China
| | | | - Zhengyan Wang
- Department of Orthopedics, Changchun University of Chinese Medicine, Changchun, China
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Abou Shousha S, Osman EM, Baheeg S, Shahine Y. Anti-IL-8 monoclonal antibodies inhibits the autophagic activity and cancer stem cells maintenance within breast cancer tumor microenvironment. Breast Dis 2024; 43:37-49. [PMID: 38552109 PMCID: PMC10977415 DOI: 10.3233/bd-230052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
BACKGROUND Breast cancer tumor microenvironment (TME) is a promising target for immunotherapy. Autophagy, and cancer stem cells (CSCs) maintenance are essential processes involved in tumorigenesis, tumor survival, invasion, and treatment resistance. Overexpression of angiogenic chemokine interleukin-8 (IL-8) in breast cancer TME is associated with oncogenic signaling pathways, increased tumor growth, metastasis, and poor prognosis. OBJECTIVE Thus, we aimed to investigate the possible anti-tumor effect of neutralizing antibodies against IL-8 by evaluating its efficacy on autophagic activity and breast CSC maintenance. METHODS IL-8 monoclonal antibody supplemented tumor tissue culture systems from 15 females undergoing mastectomy were used to evaluate the expression of LC3B as a specific biomarker of autophagy and CD44, CD24 as cell surface markers of breast CSCs using immunofluorescence technique. RESULTS Our results revealed that anti-IL-8 mAb significantly decreased the level of LC3B in the cultured tumor tissues compared to its non-significant decrease in the normal breast tissues.Anti-IL-8 mAb also significantly decreased the CD44 expression in either breast tumors or normal cultured tissues. While it caused a non-significant decrease in CD24 expression in cultured breast tumor tissue and a significant decrease in its expression in the corresponding normal ones. CONCLUSIONS Anti-IL-8 monoclonal antibody exhibits promising immunotherapeutic properties through targeting both autophagy and CSCs maintenance within breast cancer TME.
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Affiliation(s)
- Seham Abou Shousha
- Immunology and Allergy Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Eman M. Osman
- Immunology and Allergy Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Suzan Baheeg
- Immunology and Allergy Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Yasmine Shahine
- Faculty of Pharmacy, Department of Microbiology & Immunology, Pharos University in Alexandria, Alexandria, Egypt
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Hu H, Li B, Wang J, Tan Y, Xu M, Xu W, Lu H. New advances into cisplatin resistance in head and neck squamous carcinoma: Mechanisms and therapeutic aspects. Biomed Pharmacother 2023; 163:114778. [PMID: 37137185 DOI: 10.1016/j.biopha.2023.114778] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/20/2023] [Accepted: 04/23/2023] [Indexed: 05/05/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) arises from the interplay of multiple factors, such as smoking, alcohol consumption, and viral infections. Cisplatin-based concurrent radiotherapy regimens represent the first-line treatment for advanced HNSCC cases. However, cisplatin resistance significantly contributes to poor prognoses in HNSCC patients, making it crucial to unravel the underlying mechanisms to overcome this resistance. The complexity of cisplatin resistance in HNSCC involves cancer stem cells, autophagy, epithelial-mesenchymal transition, drug efflux, and metabolic reprogramming. Recent advances in nanodrug delivery systems, combined with existing small-molecule inhibitors and innovative genetic technologies, have opened new therapeutic avenues for addressing cisplatin resistance in HNSCC. This review systematically summarizes research progress from the past five years on cisplatin resistance in HNSCC, with a particular focus on the roles of cancer stem cells and autophagy. Additionally, potential future treatment strategies to overcome cisplatin resistance are discussed, including the targeting of cancer stem cells or autophagy through nanoparticle-based drug delivery systems. Furthermore, the review highlights the prospects and challenges associated with nanodelivery platforms in addressing cisplatin resistance in HNSCC.
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Affiliation(s)
- Hanlin Hu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Bo Li
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Junke Wang
- Department of Cardiology, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao, China.
| | - Ye Tan
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Mingjin Xu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Wenhua Xu
- Institute of Regenerative Medicine and Laboratory Technology Innovation, Qingdao University, Qingdao, China.
| | - Haijun Lu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
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Wang H, Guo M, Wei H, Chen Y. Targeting p53 pathways: mechanisms, structures, and advances in therapy. Signal Transduct Target Ther 2023; 8:92. [PMID: 36859359 PMCID: PMC9977964 DOI: 10.1038/s41392-023-01347-1] [Citation(s) in RCA: 332] [Impact Index Per Article: 166.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 12/19/2022] [Accepted: 02/07/2023] [Indexed: 03/03/2023] Open
Abstract
The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the "guardian of the genome". Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an "undruggable" target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.
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Affiliation(s)
- Haolan Wang
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Ming Guo
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Hudie Wei
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
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Abstract
PURPOSE OF REVIEW The unique properties of cancer stem cells (CSCs) make lung cancer untargetable for quite an extended period. The functional mechanism of this cell type has been illustrated step by step. However, the outcomes of lung cancer patients are still lower than expected clinically. The attempts made by scientists to make challenge history against stemness maintenance of lung cancer cells and their druggable targets are worth elucidating. RECENT FINDINGS Many agents, including the Bispecific T-cell engager (BiTE) and AMG 119 targeting DLL3-positive cells, are a tremendous breakthrough in the preclinical and clinical treatment of SCLC. More studies focus on targeting CSCs to overcome TKI resistance in NSCLC. The combo targeting of CSC and the immune microenvironment can favor the treatment of lung cancer patients. SUMMARY The current review elucidates the characteristics and related regulating pathways of lung CSCs from essential to preclinical research. We retrospectively introduce an update on the clinical development of therapeutics targeting CSC-associated developmental signaling pathways and discuss the opportunities to target CSC-immune interactions in lung cancer.
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Mutant p53 in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis 2022; 13:974. [PMID: 36400749 PMCID: PMC9674619 DOI: 10.1038/s41419-022-05408-1] [Citation(s) in RCA: 172] [Impact Index Per Article: 57.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 11/02/2022] [Accepted: 11/04/2022] [Indexed: 11/19/2022]
Abstract
TP53, a crucial tumor suppressor gene, is the most commonly mutated gene in human cancers. Aside from losing its tumor suppressor function, mutant p53 (mutp53) often acquires inherent, novel oncogenic functions, which is termed "gain-of-function". Emerging evidence suggests that mutp53 is highly associated with advanced malignancies and poor prognosis, which makes it a target for development of novel cancer therapies. Herein, we provide a summary of our knowledge of the mutp53 types and mutp53 spectrum in cancers. The mechanisms of mutp53 accumulation and gain-of-function are also summarized. Furthermore, we discuss the gain-of-function of mutp53 in cancers: genetic instability, ferroptosis, microenvironment, and stemness. Importantly, the role of mutp53 in the clinic is also discussed, particularly with regard to chemotherapy and radiotherapy. Last, emphasis is given to emerging strategies on how to target mutp53 for tumor therapy. Thus, this review will contribute to better understanding of the significance of mutp53 as a target for therapeutic strategies.
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Dzul Keflee R, Hoong Leong K, Ogawa S, Bignon J, Chiang Chan M, Weng Kong K. Overview of the multifaceted resistances toward EGFR-TKIs and new chemotherapeutic strategies in non-small cell lung cancer. Biochem Pharmacol 2022; 205:115262. [PMID: 36191627 DOI: 10.1016/j.bcp.2022.115262] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 09/19/2022] [Accepted: 09/20/2022] [Indexed: 11/02/2022]
Abstract
The role of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) has been vastly studied over the last decade. This has led to the rapid development of many generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, patients treated with third-generation TKIs (osimertinib, avitinib and rociletinib) targeting the EGFR T790M mutation have shown emerging resistances and relapses. Therefore, further molecular understanding of NSCLC mutations, bypass signalling, tumour microenvironment and the existence of cancer stem cells to overcome such resistances is warranted. This will pave the way for designing novel and effective chemotherapies to improve patients' overall survival. In this review, we provide an overview of the multifaceted mechanism of resistances towards EGFR-TKIs, as well as the challenges and perspectives that should be addressed in strategising chemotherapeutic treatments to overcome the ever evolving and adaptive nature of NSCLC.
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Affiliation(s)
- Rashidi Dzul Keflee
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Kok Hoong Leong
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
| | - Satoshi Ogawa
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, Malaysia
| | - Jerome Bignon
- Institut de Chimie des Substances Naturelles CNRS UPR 2301, Université Paris Saclay, Gif-sur-Yvette, France
| | - Mun Chiang Chan
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Kin Weng Kong
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
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Hao S, Li F, Liu Y, Yang Q, Li Q, Zhang W, Wang C. Phycocyanin diminishes the viability of non-small cell lung cancer cells via induction of autophagy. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Identification of an Autophagy-Related Signature Based on Whole Bone Marrow Sequencing for the Prognosis and Immune Microenvironment Characterization of Multiple Myeloma. J Immunol Res 2022; 2022:3922739. [PMID: 35677537 PMCID: PMC9169202 DOI: 10.1155/2022/3922739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/21/2022] [Accepted: 05/04/2022] [Indexed: 11/17/2022] Open
Abstract
Myeloma (MM) is a malignant plasma cell disorder, which is incurable owing to its drug resistance. Autophagy performs an integral function in homeostasis, survival, and drug resistance in multiple myeloma (MM). Therefore, the purpose of the present research was to identify potential autophagy-related genes (ARGs) in patients with MM. We downloaded the transcriptomic data (GSE136400) of patients with MM, as well as the corresponding clinical data from the Gene Expression Omnibus (GEO); the patients were classified at random into two groups in a ratio of 6: 4, with 212 samples in the training dataset and 142 samples in the test dataset. Both multivariate and univariate Cox regression analyses were performed to identify autophagy-related genes. The univariate Cox regression analysis demonstrated that 26 ARGs had a significant correlation with overall survival (OS). We constructed an autophagy-related risk prognostic model based on six ARGs: EIF2AK2 (ENSG00000055332), KIF5B (ENSG00000170759), MYC (ENSG00000136997), NRG2 (ENSG00000158458), PINK1 (ENSG00000158828), and VEGFA (ENSG00000112715) using LASSO-Cox regression analysis to predict risk outcomes, which revealed substantially shortened OS duration in the high-risk cohort in contrast with that in the low-risk cohort. Therefore, the ARG-based model significantly predicted the MM patients’ prognoses and was verified in an internal test set. Differentially expressed genes were found to be predominantly enriched in pathways associated with inflammation and immune regulation. Immune infiltration of tumor cells resulted in the formation of a strong immunosuppressive microenvironment in high-risk patients. The potential therapeutic targets of ARGs were subsequently analyzed via protein–drug network analysis. Therefore, a prognostic model for MM was established via a comprehensive analysis of ARGs, through using the clinical models; we have further revealed the molecular landscape features of multiple myeloma.
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Autophagy and EMT in cancer and metastasis: Who controls whom? Biochim Biophys Acta Mol Basis Dis 2022; 1868:166431. [PMID: 35533903 DOI: 10.1016/j.bbadis.2022.166431] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/10/2022] [Accepted: 05/02/2022] [Indexed: 02/06/2023]
Abstract
Metastasis consists of hallmark events, including Epithelial-Mesenchymal Transition (EMT), angiogenesis, initiation of inflammatory tumor microenvironment, and malfunctions in apoptosis. Autophagy is known to play a pivotal role in the metastatic process. Autophagy has pulled researchers towards it in recent times because of its dual role in the maintenance of cancer cells. Evidence states that cells undergoing EMT need autophagy in order to survive during migration and dissemination. Additionally, it orchestrates EMT markers in certain cancers. On the other side of the coin, autophagy plays an oncosuppressive role in impeding early metastasis. This review aims to project the interrelationship between autophagy and EMT. Targeting EMT via autophagy as a useful strategy is discussed in this review. Furthermore, for the first time, we have covered the possible reciprocating roles of EMT and autophagy and its consequences in cancer metastasis.
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Guo W, Du K, Luo S, Hu D. Recent Advances of Autophagy in Non-Small Cell Lung Cancer: From Basic Mechanisms to Clinical Application. Front Oncol 2022; 12:861959. [PMID: 35600411 PMCID: PMC9115384 DOI: 10.3389/fonc.2022.861959] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 04/04/2022] [Indexed: 12/27/2022] Open
Abstract
Lung cancer is characterized by the most common oncological disease and leading cause of cancer death worldwide, of which a group of subtypes known as non-small cell lung cancer (NSCLC) accounts for approximately 85%. In the past few decades, important progression in the therapies of NSCLC has enhanced our understanding of the biology and progression mechanisms of tumor. The application of immunotherapy and small molecule tyrosine kinase inhibitors has brought significant clinical benefits in certain patients. However, early metastasis and the emergence of resistance to antitumor therapy have resulted in the relatively low overall cure and survival rates for NSCLC. Autophagy is a conserved process that allows cells to recycle unused or damaged organelles and cellular components. It has been reported to be related to the progression of NSCLC and resistance to targeted therapy and cytotoxic chemotherapy. Therefore, autophagy is considered as a potential therapeutic target for NSCLC. Mounting results have been reported about the combination of tyrosine kinase inhibitors and inhibitors of autophagy in models of NSCLC. This review aims to provide a comprehensive review on the roles of autophagy in NSCLC, focusing on related clinical data of agents that regulate autophagy in NSCLC. Furthermore, this study will provide a theoretical basis for further improvement of autophagy-based cancer therapy.
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Affiliation(s)
- Weina Guo
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Keye Du
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shanshan Luo
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Desheng Hu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Biological Targeted Therapy, The Ministry of Education, Wuhan, China
- Department of immunology, Hubei Clinical Research Center of Cancer Immunotherapy, Wuhan, China
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15
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Xiao W, Geng W, Zhou M, Xu J, Wang S, Huang Q, Sun Y, Li Y, Yang G, Jin Y. POU6F1 cooperates with RORA to suppress the proliferation of lung adenocarcinoma by downregulation HIF1A signaling pathway. Cell Death Dis 2022; 13:427. [PMID: 35504868 PMCID: PMC9065044 DOI: 10.1038/s41419-022-04857-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 04/08/2022] [Accepted: 04/13/2022] [Indexed: 12/14/2022]
Abstract
Lung adenocarcinoma (LUAD) represents the most frequently diagnosed histological subtype of non-small cell lung cancer with the highest mortality worldwide. Transcriptional dysregulation is a hallmark of nearly all kinds of cancers. In the study, we identified that the POU domain, class 6, transcription factor 1 (POU6F1), a member of the POU family of transcription factors, was closely associated with tumor stage and death in LUAD. We revealed that POU6F1 was downregulated in LUAD tissues and downregulated POU6F1 was predictive of an unfavorable prognosis in LUAD patients. In vitro assays, including CCK8, soft agar, transwell, clone formation, wound-healing assay, and nude mouse xenograft model all revealed that POU6F1 inhibited the growth and invasion of LUAD cells. Mechanistically, POU6F1 bound and stabilized retinoid-related orphan receptor alpha (RORA) to exert the transcriptional inhibition of hypoxia-inducible factor 1-alpha (HIF1A) and alter the expression of HIF1A signaling pathway-associated genes, including ENO1, PDK1, and PRKCB, thereby leading to the suppression of LUAD cells. Collectively, these results demonstrated the suppressive role of POU6F1/RORA in the progression of LUAD and may potentially be used as a target for the treatment of LUAD.
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Affiliation(s)
- Wenjing Xiao
- grid.33199.310000 0004 0368 7223Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Wei Geng
- grid.33199.310000 0004 0368 7223Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Mei Zhou
- grid.33199.310000 0004 0368 7223Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Juanjuan Xu
- grid.33199.310000 0004 0368 7223Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Sufei Wang
- grid.33199.310000 0004 0368 7223Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Qi Huang
- grid.33199.310000 0004 0368 7223Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Yice Sun
- grid.33199.310000 0004 0368 7223Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Yumei Li
- grid.33199.310000 0004 0368 7223Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Guanghai Yang
- grid.33199.310000 0004 0368 7223Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Yang Jin
- grid.33199.310000 0004 0368 7223Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
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16
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Sun Z, Liu D, Zeng B, Zhao Q, Li X, Chen H, Wang J, Rosie Xing H. Sec23a inhibits the self-renewal of melanoma cancer stem cells via inactivation of ER-phagy. Cell Commun Signal 2022; 20:22. [PMID: 35236368 PMCID: PMC8889648 DOI: 10.1186/s12964-022-00827-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 01/07/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The genesis and developments of solid tumors, analogous to the renewal of healthy tissues, are driven by a subpopulation of dedicated stem cells, known as cancer stem cells (CSCs), that exhibit long-term clonal repopulation and self-renewal capacity. CSCs may regulate tumor initiation, growth, dormancy, metastasis, recurrence and chemoresistance. While autophagy has been proposed as a regulator of the stemness of CSCs, the underlying mechanisms requires further elucidation. METHODS The CSC component in human melanoma cell lines M14 and A375 was isolated and purified by repetitive enrichments for cells that consistently display anchorage-independent spheroid growth. The stemness properties of the CSCs were confirmed in vitro by the expressions of stemness marker genes, the single-cell cloning assay and the serial spheroid formation assay. Subcutaneous tumor transplantation assay in BALB/c nude mice was performed to test the stemness properties of the CSCs in vivo. The autophagic activity was confirmed by the protein level of LC3 and P62, mRFP-LC3B punta and cytoplasmic accumulation of autolysosomes. The morphology of ER was detected with transmission electron microscopy. RESULTS In the present study, by employing stable CSC cell lines derived from human melanoma cell lines M14 and A375, we show for the first time that Sec23a inhibits the self-renewal of melanoma CSCs via inactivation of ER-phagy. Mechanistically, inhibition of Sec23a reduces ER stress and consequently FAM134B-induced ER-phagy. Furthermore, TCGA data mining and analysis show that Sec23a is a favorable diagnostic and prognostic marker for human skin cutaneous melanoma. CONCLUSION This study has elucidated a new mechanism underlying the regulation of autophagy on stemness, i.e. CSCs can exploit the SEC23A/ER-stress/FAM134B/ER-phagy axis for the self-renewal. These observations provide new ideas for exploration of the regulatory network of CSC self-renewal to develop CSCs-based therapy strategies for malignant tumors. Video Abstract.
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Affiliation(s)
- Zhiwei Sun
- Institute of Life Sciences, Chongqing Medical University, 1 Yi Xue Yuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
- The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
| | - Doudou Liu
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, College of Biomedical Engineering, Chongqing Medical University, 1 Yi Xue Yuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
| | - Bin Zeng
- Institute of Life Sciences, Chongqing Medical University, 1 Yi Xue Yuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
| | - Qiting Zhao
- Institute of Life Sciences, Chongqing Medical University, 1 Yi Xue Yuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
| | - Xiaoshuang Li
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, College of Biomedical Engineering, Chongqing Medical University, 1 Yi Xue Yuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
| | - Hao Chen
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, College of Biomedical Engineering, Chongqing Medical University, 1 Yi Xue Yuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
| | - Jianyu Wang
- Institute of Life Sciences, Chongqing Medical University, 1 Yi Xue Yuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
| | - H. Rosie Xing
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, College of Biomedical Engineering, Chongqing Medical University, 1 Yi Xue Yuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
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Rahman MA, Park MN, Rahman MDH, Rashid MM, Islam R, Uddin MJ, Hannan MA, Kim B. p53 Modulation of Autophagy Signaling in Cancer Therapies: Perspectives Mechanism and Therapeutic Targets. Front Cell Dev Biol 2022; 10:761080. [PMID: 35155422 PMCID: PMC8827382 DOI: 10.3389/fcell.2022.761080] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 01/04/2022] [Indexed: 12/22/2022] Open
Abstract
The key tumor suppressor protein p53, additionally known as p53, represents an attractive target for the development and management of anti-cancer therapies. p53 has been implicated as a tumor suppressor protein that has multiple aspects of biological function comprising energy metabolism, cell cycle arrest, apoptosis, growth and differentiation, senescence, oxidative stress, angiogenesis, and cancer biology. Autophagy, a cellular self-defense system, is an evolutionarily conserved catabolic process involved in various physiological processes that maintain cellular homeostasis. Numerous studies have found that p53 modulates autophagy, although the relationship between p53 and autophagy is relatively complex and not well understood. Recently, several experimental studies have been reported that p53 can act both an inhibitor and an activator of autophagy which depend on its cellular localization as well as its mode of action. Emerging evidences have been suggested that the dual role of p53 which suppresses and stimulates autophagy in various cencer cells. It has been found that p53 suppression and activation are important to modulate autophagy for tumor promotion and cancer treatment. On the other hand, activation of autophagy by p53 has been recommended as a protective function of p53. Therefore, elucidation of the new functions of p53 and autophagy could contribute to the development of novel therapeutic approaches in cancer biology. However, the underlying molecular mechanisms of p53 and autophagy shows reciprocal functional interaction that is a major importance for cancer treatment and manegement. Additionally, several synthetic drugs and phytochemicals have been targeted to modulate p53 signaling via regulation of autophagy pathway in cancer cells. This review emphasizes the current perspectives and the role of p53 as the main regulator of autophagy-mediated novel therapeutic approaches against cancer treatment and managements.
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Affiliation(s)
- Md Ataur Rahman
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
- Global Biotechnology & Biomedical Research Network (GBBRN), Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Islamic University, Kushtia, Bangladesh
- *Correspondence: Md Ataur Rahman, ; Bonglee Kim,
| | - Moon Nyeo Park
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - MD Hasanur Rahman
- Department of Biotechnology and Genetic Engineering, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
- ABEx Bio-Research Center, Dhaka, Bangladesh
| | - Md Mamunur Rashid
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States
| | - Rokibul Islam
- Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Islamic University, Kushtia, Bangladesh
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, South Korea
| | - Md Jamal Uddin
- ABEx Bio-Research Center, Dhaka, Bangladesh
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Md Abdul Hannan
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
- *Correspondence: Md Ataur Rahman, ; Bonglee Kim,
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Wang X, Lee J, Xie C. Autophagy Regulation on Cancer Stem Cell Maintenance, Metastasis, and Therapy Resistance. Cancers (Basel) 2022; 14:cancers14020381. [PMID: 35053542 PMCID: PMC8774167 DOI: 10.3390/cancers14020381] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/09/2022] [Accepted: 01/10/2022] [Indexed: 02/08/2023] Open
Abstract
Simple Summary Certain types of cancer have higher relapse rates compared to others, and cancer stem cells (CSCs) have been shown as the main drivers of cancer relapse and cancer severity. This subpopulation of cells displays stem-like characteristics which bolster tumorigenesis along with metastasis and lead to poorer prognoses. Autophagy has been studied as a mechanism by which CSCs maintain stemness and acquire resistance to chemotherapy and radiation. The aim of this review is to condense and organize what has been recently published on the connection between cancer stem cells (CSCs) and autophagy. Multiple studies on autophagy have suggested that the pathway is a double-edged sword, which can either undermine or enhance CSC characteristics depending on interactions with different pathways. Thus, future research should investigate regulation of autophagy in combination with traditional cancer therapies as a possible method to effectively eliminate CSCs and minimize cancer relapse. Abstract Cancer stem cells (CSCs) are a subset of the tumor population that play critical roles in tumorigenicity, metastasis, and relapse. A key feature of CSCs is their resistance to numerous therapeutic strategies which include chemotherapy, radiation, and immune checkpoint inhibitors. In recent years, there is a growing body of literature that suggests a link between CSC maintenance and autophagy, a mechanism to recycle intracellular components during moments of environmental stress, especially since CSCs thrive in a tumor microenvironment that is plagued with hypoxia, acidosis, and lack of nutrients. Autophagy activation has been shown to aid in the upkeep of a stemness state along with bolstering resistance to cancer treatment. However, recent studies have also suggested that autophagy is a double-edged sword with anti-tumorigenic properties under certain circumstances. This review summarizes and integrates what has been published in the literature in terms of what role autophagy plays in stemness maintenance of CSCs and suggests that there is a more complex interplay between autophagy and apoptosis which involves multiple pathways of regulation. Future cancer therapy strategies are needed to eradicate this resistant subset of the cell population through autophagy regulation.
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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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20
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Shen S, Wang R, Qiu H, Li C, Wang J, Xue J, Tang Q. Development of an Autophagy-Based and Stemness-Correlated Prognostic Model for Hepatocellular Carcinoma Using Bulk and Single-Cell RNA-Sequencing. Front Cell Dev Biol 2021; 9:743910. [PMID: 34820373 PMCID: PMC8606524 DOI: 10.3389/fcell.2021.743910] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/11/2021] [Indexed: 01/10/2023] Open
Abstract
Accumulating evidence has proved that autophagy serves as a tumor promoter in formed malignancies, and the autophagy-related prognostic signatures have been constructed as clinical tools to predict prognosis in many high-mortality cancers. Autophagy-related genes have participated in the development and metastasis of hepatocellular carcinoma (HCC), but the understanding of their prognostic value is limited. Thereafter, LIMMA and survival analysis were conducted in both ICGC and TCGA databases and a total of 10 hub autophagy-related genes, namely, NPC1, CDKN2A, RPTOR, SPHK1, HGS, BIRC5, SPNS1, BAK1, ATIC, and MAPK3, were collected. Then, GO, KEGG, correlation, consensus, and PCA analyses were utilized to reveal their potential targeted role in HCC treatment. Single-cell RNA-seq of cancer stem cells also indicated that there was a positive correlation between these genes and stemness. In parallel, we applied univariate, LASSO, and multivariate regression analyses to study the autophagy-related genes and finally proposed that ATIC and BIRC5 were the valuable prognostic indicators of HCC. The signature based on ATIC and BIRC5 exhibited moderate power for predicting the survival of HCC in the ICGC cohort, and its efficacy was further validated in the TCGA cohort. Taken together, we suggested that 10 aforementioned hub genes are promising therapeutic targets of HCC and the ATIC/BIRC5 prognostic signature is a practical prognostic indicator for HCC patients.
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Affiliation(s)
- Shengwei Shen
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Rui Wang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hua Qiu
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chong Li
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jinghan Wang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Junli Xue
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qinghe Tang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
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21
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The Emerging Roles of Autophagy in Human Diseases. Biomedicines 2021; 9:biomedicines9111651. [PMID: 34829881 PMCID: PMC8615641 DOI: 10.3390/biomedicines9111651] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/03/2021] [Accepted: 11/05/2021] [Indexed: 01/18/2023] Open
Abstract
Autophagy, a process of cellular self-digestion, delivers intracellular components including superfluous and dysfunctional proteins and organelles to the lysosome for degradation and recycling and is important to maintain cellular homeostasis. In recent decades, autophagy has been found to help fight against a variety of human diseases, but, at the same time, autophagy can also promote the procession of certain pathologies, which makes the connection between autophagy and diseases complex but interesting. In this review, we summarize the advances in understanding the roles of autophagy in human diseases and the therapeutic methods targeting autophagy and discuss some of the remaining questions in this field, focusing on cancer, neurodegenerative diseases, infectious diseases and metabolic disorders.
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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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Zhang X, Cao Y, Chen L. Construction of a prognostic signature of autophagy-related lncRNAs in non-small-cell lung cancer. BMC Cancer 2021; 21:921. [PMID: 34391383 PMCID: PMC8364711 DOI: 10.1186/s12885-021-08654-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 07/29/2021] [Indexed: 01/18/2023] Open
Abstract
Background Autophagy inhibits tumorigenesis by limiting inflammation. LncRNAs regulate gene expression at various levels as RNAs; thus, both autophagy and lncRNAs are closely related to the occurrence and development of tumours. Methods A total of 232 autophagy-related genes were used to construct a coexpression network to extract autophagy-related lncRNAs. A prognostic signature was constructed by multivariate regression analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was applied to analyse enrichment in cancer-related pathways. Immune infiltration analysis was used to analyse the relationship between the prognostic signature and the tumour microenvironment. Results Nine autophagy-related lncRNAs were used to construct a prognostic model for non-small-cell lung cancer. The median risk score was used to discriminate the high- and low-risk groups, and the low-risk group was found to have better survival. Because KEGG pathway analysis showed that the prognostic signature was enriched in some immune pathways, further analysis of immune infiltration was conducted, and it was found that the prognostic signature did play a unique role in the immune microenvironment. Additionally, the prognostic signature was associated with clinical factors. Conclusion We constructed a prognostic model of autophagy-related lncRNAs that can predict the prognosis of non-small-cell lung cancer.
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Affiliation(s)
- Xinyang Zhang
- Department of Pathology Anatomy, Medical College of Nantong University, Nantong University, Nantong, 226001, Jiangsu, China
| | - Yu Cao
- Third People's Hospital of Nantong, Nantong, 226001, Jiangsu, China
| | - Li Chen
- Department of Pathology Anatomy, Medical College of Nantong University, Nantong University, Nantong, 226001, Jiangsu, China.
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Chen S, Wang W, Tan HY, Lu Y, Li Z, Qu Y, Wang N, Wang D. Role of Autophagy in the Maintenance of Stemness in Adult Stem Cells: A Disease-Relevant Mechanism of Action. Front Cell Dev Biol 2021; 9:715200. [PMID: 34414192 PMCID: PMC8369482 DOI: 10.3389/fcell.2021.715200] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/15/2021] [Indexed: 01/07/2023] Open
Abstract
Autophagy is an intracellular scavenging mechanism induced to eliminate damaged, denatured, or senescent macromolecular substances and organelles in the body. The regulation of autophagy plays essential roles in the processes of cellular homeostasis and senescence. Dysregulated autophagy is a common feature of several human diseases, including cancers and neurodegenerative disorders. The initiation and development of these disorders have been shown to be associated with the maintenance of disease-specific stem cell compartments. In this review, we summarize recent advances in our understanding of the role of autophagy in the maintenance of stemness. Specifically, we focus on the intersection between autophagy and adult stem cells in the initiation and progression of specific diseases. Accordingly, this review highlights the role of autophagy in stemness maintenance from the perspective of disease-associated mechanisms, which may be fundamental to our understanding of the pathogeneses of human diseases and the development of effective therapies.
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Affiliation(s)
- Shanshan Chen
- School of Life Sciences, Jilin University, Changchun, China
| | - Wenqi Wang
- School of Life Sciences, Jilin University, Changchun, China
| | - Hor-Yue Tan
- Centre for Chinese Herbal Medicine Drug Development, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Yuanjun Lu
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Zhiping Li
- School of Life Sciences, Jilin University, Changchun, China
| | - Yidi Qu
- School of Life Sciences, Jilin University, Changchun, China
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Di Wang
- School of Life Sciences, Jilin University, Changchun, China
- Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun, China
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25
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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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Liu D, Sun Z, Ye T, Li J, Zeng B, Zhao Q, Wang J, Xing HR. The mitochondrial fission factor FIS1 promotes stemness of human lung cancer stem cells via mitophagy. FEBS Open Bio 2021; 11:1997-2007. [PMID: 34051059 PMCID: PMC8406485 DOI: 10.1002/2211-5463.13207] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/11/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022] Open
Abstract
Mitophagy, a form of autophagy, plays a role in cancer development, progression and recurrence. Cancer stem cells (CSCs) also play a key role in these processes, although it not known whether mitophagy can regulate the stemness of CSCs. Here, we employed the A549-SD human non-small cell lung adenocarcinoma CSC model that we have developed and characterized to investigate the effect of mitophagy on the stemness of CSCs. We observed a positive relationship between mitophagic activity and the stemness of lung CSCs. At the mechanistic level, our results suggest that augmentation of mitophagy in lung CSCs can be induced by FIS1 through mitochondrial fission. In addition, we assessed the clinical relevance of FIS1 in lung adenocarcinoma using The Cancer Genome Atlas database. An elevation in FIS1, when observed together with other prognostic markers for lung cancer progression, was found to correlate with shorter overall survival.
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Affiliation(s)
- Doudou Liu
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, School of Biomedical Engineering, Chongqing Medical University, China
| | - Zhiwei Sun
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, School of Biomedical Engineering, Chongqing Medical University, China
| | - Ting Ye
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, School of Biomedical Engineering, Chongqing Medical University, China
| | - Jingyuan Li
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, School of Biomedical Engineering, Chongqing Medical University, China
| | - Bin Zeng
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, School of Biomedical Engineering, Chongqing Medical University, China
| | - Qiting Zhao
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, School of Biomedical Engineering, Chongqing Medical University, China
| | - Jianyu Wang
- Institute of Life Sciences, Chongqing Medical University, China
| | - Hongmei Rosie Xing
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, School of Biomedical Engineering, Chongqing Medical University, China
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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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