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Gummadi R, Nori LP, Pindiprolu SKSS, Dasari N, Ahmad Z, Km M. Nanomaterials for delivery of drugs and genes to disrupt notch signaling pathway in breast cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04082-2. [PMID: 40392305 DOI: 10.1007/s00210-025-04082-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Accepted: 03/20/2025] [Indexed: 05/22/2025]
Abstract
Breast cancer, marked by considerable heterogeneity and intricate molecular subgroups, poses substantial obstacles to therapy. Epithelial-mesenchymal transition (EMT) and the existence of tumor-initiating cells (TICs) facilitate treatment resistance, metastasis, and worse prognosis. The Notch signaling system has garnered significant interest for its involvement in promoting epithelial-mesenchymal transition (EMT), maintaining tumor-initiating cells (TIC), and facilitating cancer progression, especially in truculent subtypes such as triple-negative breast cancer (TNBC). Targeting the Notch system represents a promising therapeutic strategy; nevertheless, traditional inhibitors frequently encounter obstacles, including inadequate selectivity and bioavailability. Nanocarrier-based drug delivery systems provide novel therapeutic strategies to these difficulties by augmenting the targeted delivery of Notch inhibitors and enhancing therapeutic efficacy. Solid lipid nanoparticles (SLNs), polymeric nanoparticles, lipid-based nanocarriers, and micelles exhibit promise in delivering Notch inhibitors to neoplastic cells, altering the Notch signaling pathway, and surmounting drug resistance. This review examines recent breakthroughs in nanocarrier systems aimed at the Notch signaling pathway in breast cancer, highlighting the therapeutic potential of integrating nanomedicine with Notch inhibition to disrupt epithelial-mesenchymal transition (EMT), tumor-initiating cells (TICs), and metastasis, thereby enhancing clinical outcomes.
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Affiliation(s)
- Ramakrishna Gummadi
- School of Pharmacy, Aditya University, Surampalem, 533437, India
- Department of Pharmaceutics, Shri Vishnu College of Pharmacy, Bhimavaram, India
| | | | | | - Nagasen Dasari
- School of Pharmacy, Aditya University, Surampalem, 533437, India
| | - Zubair Ahmad
- Centre of Bee Research and Its Products, King Khalid University, P.O. Box 9004, Abha, 61413, Saudi Arabia
- Applied College, Mahala Campus, King Khalid University, P.O. Box 9004, Abha, 61413, Saudi Arabia
| | - Muhasina Km
- Department of Pharmaceutical Analysis, Prime College of Pharmacy, Erattayal, Kodumbu, Palakkad, Kerala, 678551, India
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Varisli L, Zoumpourlis P, Spandidos DA, Zoumpourlis V, Vlahopoulos S. ALDH1A1 in breast cancer: A prospective target to overcome therapy resistance (Review). Oncol Lett 2025; 29:213. [PMID: 40093866 PMCID: PMC11905208 DOI: 10.3892/ol.2025.14959] [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: 12/17/2024] [Accepted: 02/06/2025] [Indexed: 03/19/2025] Open
Abstract
The expression of cytosolic aldehyde dehydrogenases (ALDHs), which mediate the last step in the pathway of the synthesis of all-trans retinoic acid, is dysregulated in various types of human cancer, and has been associated with the development of cancer stem cells (CSCs) in solid tumors and hematological malignancies. CSCs are considered a minor fraction of cancer cells with the capacity to initiate neoplastic tumors. ALDH1A1 serves a crucial role in the emergence of the CSC phenotype, induces the malignant behavior of cancer cells and promotes treatment resistance. Notably, ALDH1A1-induced therapy resistance is not exclusive to just one group of drugs, but affects diverse types of drugs that use different mechanisms to kill cells. This diversity of drug resistance-inducing effects is associated with the stemness-supporting functions of ALDH1A1. The inhibition of ALDH1A1 activity using chemicals or the depletion of ALDH1A1 via genetic approaches, such as the use of small interfering RNA, can overcome diverse pathways of therapy resistance. In the context of breast cancer, it is critical that only a fraction of malignant cells are expected to manifest stem-like features, which include increased expression of ALDH1A1. From the angle of disease prognosis, the extent of the association of ALDH1A1 with increased malignant behavior and drug resistance remains to be determined through the application of cutting-edge methods that detect the expression of tracked biomarkers within tumors.
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Affiliation(s)
- Lokman Varisli
- Department of Molecular Biology and Genetics, Science Faculty, Dicle University, Diyarbakir 21280, Turkey
| | - Panagiotis Zoumpourlis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Vassilis Zoumpourlis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Spiros Vlahopoulos
- First Department of Pediatrics, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Fiorentino F, Fabbrizi E, Mai A, Rotili D. Activation and inhibition of sirtuins: From bench to bedside. Med Res Rev 2025; 45:484-560. [PMID: 39215785 PMCID: PMC11796339 DOI: 10.1002/med.22076] [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: 05/25/2022] [Revised: 07/27/2024] [Accepted: 08/04/2024] [Indexed: 09/04/2024]
Abstract
The sirtuin family comprises seven NAD+-dependent enzymes which catalyze protein lysine deacylation and mono ADP-ribosylation. Sirtuins act as central regulators of genomic stability and gene expression and control key processes, including energetic metabolism, cell cycle, differentiation, apoptosis, and aging. As a result, all sirtuins play critical roles in cellular homeostasis and organism wellness, and their dysregulation has been linked to metabolic, cardiovascular, and neurological diseases. Furthermore, sirtuins have shown dichotomous roles in cancer, acting as context-dependent tumor suppressors or promoters. Given their central role in different cellular processes, sirtuins have attracted increasing research interest aimed at developing both activators and inhibitors. Indeed, sirtuin modulation may have therapeutic effects in many age-related diseases, including diabetes, cardiovascular and neurodegenerative disorders, and cancer. Moreover, isoform selective modulators may increase our knowledge of sirtuin biology and aid to develop better therapies. Through this review, we provide critical insights into sirtuin pharmacology and illustrate their enzymatic activities and biological functions. Furthermore, we outline the most relevant sirtuin modulators in terms of their modes of action, structure-activity relationships, pharmacological effects, and clinical applications.
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Affiliation(s)
- Francesco Fiorentino
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
| | - Emanuele Fabbrizi
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
| | - Antonello Mai
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
- Pasteur Institute, Cenci‐Bolognetti FoundationSapienza University of RomeRomeItaly
| | - Dante Rotili
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
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Barsky SH, Mcphail K, Wang J, Dillard J, Beard CJ, Ye Y. True cancer stem cells exhibit relative degrees of dormancy and genomic stability. Neoplasia 2025; 60:101127. [PMID: 39847828 PMCID: PMC11795081 DOI: 10.1016/j.neo.2025.101127] [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: 12/13/2024] [Revised: 01/05/2025] [Accepted: 01/14/2025] [Indexed: 01/25/2025]
Abstract
BACKGROUND Cancer stem cells in human tumors have been defined by stem cell markers, embryonal signaling pathways and characteristic biology, ie., namely the ability to repopulate the proliferating population. However, even if these properties can be demonstrated within a tumor cell subpopulation, it does not mean that they are truly hierarchical stem cells because they could have been derived from the proliferating population in a reversible manner. METHODS Using a human PDX, Mary-X, that overall expressed a strong cancer stem cell phenotype, the study conducted both GPP-labelled retroviral transfection and fluorescent microsphere uptake studies to distinguish proliferating from dormant cells and array CGH to identify regions of amplifications (gains) and deletions (losses) on the overall Mary-X population and then applied derived probes by FISH on individual cells to identify a genomically stable subpopulation. RESULTS Whereas 97-99 % of the cells expressed retroviral GFP and not fluorescent particles and showed numerous gene amplifications and deletions, approximately 1-3 % of the cells showed the opposite. The subpopulation with the retained fluorescent microspheres and exhibiting genomic stability was significantly smaller in size than their GFP-expressing and genomically unstable counterparts. Sorting Mary-X spheroids on the basis of either CD133 or ALDH positivity further enriched for this subpopulation. CONCLUSIONS These studies indicate that a truly biological cancer stem cell subpopulation exists that exhibits both dormancy and genomic stability. This subpopulation could not have been derived from the proliferating and resulting genomically unstable population and therefore represents a truly hierarchical stem cell subpopulation capable of only unidirectional differentiation.
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Affiliation(s)
- Sanford H Barsky
- Department of Pathology, Anatomy and Cell Biology and the Clinical and Translational Research Center of Excellence, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Boulevard, Nashville, TN 37208, USA.
| | - Krista Mcphail
- Star Diagnostics Laboratories, 215 E Warm Springs Rd, Ste 108, Las Vegas, NV 89119, USA
| | - Justin Wang
- Scripps Mercy Hospital, MER 35, San Diego, CA 92103, USA
| | - Jordan Dillard
- Department of Pathology, Anatomy and Cell Biology and the Clinical and Translational Research Center of Excellence, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Boulevard, Nashville, TN 37208, USA
| | - Crystal J Beard
- Department of Pathology, Anatomy and Cell Biology and the Clinical and Translational Research Center of Excellence, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Boulevard, Nashville, TN 37208, USA
| | - Yin Ye
- Department of Pathology, Anatomy and Cell Biology and the Clinical and Translational Research Center of Excellence, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Boulevard, Nashville, TN 37208, USA
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Wang Z, Li R, Yang G, Wang Y. Cancer stem cell biomarkers and related signalling pathways. J Drug Target 2024; 32:33-44. [PMID: 38095181 DOI: 10.1080/1061186x.2023.2295222] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/10/2023] [Indexed: 12/20/2023]
Abstract
Cancer stem cells (CSCs) represent a distinct subset of neoplastic cells characterised by their heightened capacity for tumorigenesis. These cells are implicated in the facilitation of cancer metastasis, recurrence, and resistance to conventional therapeutic interventions. Extensive scientific research has been devoted to the identification of biomarkers and the elucidation of molecular mechanisms in order to improve targeted therapeutic approaches. Accurate identification of cancer stem cells based on biomarkers can provide a theoretical basis for drug combinations of malignant tumours. Targeted biomarker-based therapies also offer a silver lining for patients with advanced malignancies. This review aims comprehensively to consolidate the latest findings on CSCs biomarkers, targeted agents as well as biomarkers associated signalling pathways in well-established cancer types, thereby contributing to improved prognostic outcomes.
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Affiliation(s)
- Zhe Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Department of Infectious Disease, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Rui Li
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Guilin Yang
- Department of Infectious Disease, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Yijin Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
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Shen H, Qi X, Hu Y, Wang Y, Zhang J, Liu Z, Qin Z. Targeting sirtuins for cancer therapy: epigenetics modifications and beyond. Theranostics 2024; 14:6726-6767. [PMID: 39479446 PMCID: PMC11519805 DOI: 10.7150/thno.100667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 09/29/2024] [Indexed: 11/02/2024] Open
Abstract
Sirtuins (SIRTs) are well-known as nicotinic adenine dinucleotide+(NAD+)-dependent histone deacetylases, which are important epigenetic enzymes consisting of seven family members (SIRT1-7). Of note, SIRT1 and SIRT2 are distributed in the nucleus and cytoplasm, while SIRT3, SIRT4 and SIRT5 are localized in the mitochondria. SIRT6 and SIRT7 are distributed in the nucleus. SIRTs catalyze the deacetylation of various substrate proteins, thereby modulating numerous biological processes, including transcription, DNA repair and genome stability, metabolism, and signal transduction. Notably, accumulating evidence has recently underscored the multi-faceted roles of SIRTs in both the suppression and progression of various types of human cancers. Crucially, SIRTs have been emerging as promising therapeutic targets for cancer therapy. Thus, in this review, we not only present an overview of the molecular structure and function of SIRTs, but elucidate their intricate associations with oncogenesis. Additionally, we discuss the current landscape of small-molecule activators and inhibitors targeting SIRTs in the contexts of cancer and further elaborate their combination therapies, especially highlighting their prospective utility for future cancer drug development.
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Affiliation(s)
- Hui Shen
- Department of Respiratory and Critical Care Medicine, Department of Outpatient, The First Hospital of China Medical University, Shenyang 110001, China
| | - Xinyi Qi
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Yue Hu
- Department of Respiratory and Critical Care Medicine, Department of Outpatient, The First Hospital of China Medical University, Shenyang 110001, China
| | - Yi Wang
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
- No. 989 Hospital of Joint Logistic Support Force of PLA, Luoyang 471031, China
| | - Jin Zhang
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Zhongyu Liu
- No. 989 Hospital of Joint Logistic Support Force of PLA, Luoyang 471031, China
| | - Zheng Qin
- Department of Respiratory and Critical Care Medicine, Department of Outpatient, The First Hospital of China Medical University, Shenyang 110001, China
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Zhou M, Wei L, Lu R. Emerging role of sirtuins in non‑small cell lung cancer (Review). Oncol Rep 2024; 52:127. [PMID: 39092574 PMCID: PMC11304160 DOI: 10.3892/or.2024.8786] [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: 04/04/2024] [Accepted: 07/15/2024] [Indexed: 08/04/2024] Open
Abstract
Non‑small cell lung cancer (NSCLC) is a highly prevalent lung malignancy characterized by insidious onset, rapid progression and advanced stage at the time of diagnosis, making radical surgery impossible. Sirtuin (SIRT) is a histone deacetylase that relies on NAD+ for its function, regulating the aging process through modifications in protein activity and stability. It is intricately linked to various processes, including glycolipid metabolism, inflammation, lifespan regulation, tumor formation and stress response. An increasing number of studies indicate that SIRTs significantly contribute to the progression of NSCLC by regulating pathophysiological processes such as energy metabolism, autophagy and apoptosis in tumor cells through the deacetylation of histones or non‑histone proteins. The present review elaborates on the roles of different SIRTs and their mechanisms in NSCLC, while also summarizing novel therapeutic agents based on SIRTs. It aims to present new ideas and a theoretical basis for NSCLC treatment.
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Affiliation(s)
- Min Zhou
- Department of Cardiothoracic Surgery, Chongqing University Central Hospital, Chongqing 400014, P.R. China
- Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing 400014, P.R. China
| | - Lin Wei
- Department of Cardiothoracic Surgery, Chongqing University Central Hospital, Chongqing 400014, P.R. China
- Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing 400014, P.R. China
| | - Renfu Lu
- Department of Cardiothoracic Surgery, Chongqing University Central Hospital, Chongqing 400014, P.R. China
- Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing 400014, P.R. China
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8
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Esposito M, Amory JK, Kang Y. The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes. J Exp Med 2024; 221:e20240519. [PMID: 39133222 PMCID: PMC11318670 DOI: 10.1084/jem.20240519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 07/13/2024] [Accepted: 07/26/2024] [Indexed: 08/13/2024] Open
Abstract
The retinoid nuclear receptor pathway, activated by the vitamin A metabolite retinoic acid, has been extensively investigated for over a century. This study has resulted in conflicting hypotheses about how the pathway regulates health and how it should be pharmaceutically manipulated. These disagreements arise from a fundamental contradiction: retinoid agonists offer clear benefits to select patients with rare bone growth disorders, acute promyelocytic leukemia, and some dermatologic diseases, yet therapeutic retinoid pathway activation frequently causes more harm than good, both through acute metabolic dysregulation and a delayed cancer-promoting effect. In this review, we discuss controlled clinical, mechanistic, and genetic data to suggest several disease settings where inhibition of the retinoid pathway may be a compelling therapeutic strategy, such as solid cancers or metabolic syndromes, and also caution against continued testing of retinoid agonists in cancer patients. Considerable evidence suggests a central role for retinoid regulation of immunity and metabolism, with therapeutic opportunities to antagonize retinoid signaling proposed in cancer, diabetes, and obesity.
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Affiliation(s)
- Mark Esposito
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
- Kayothera, Inc , Seattle, WA, USA
| | | | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
- Ludwig Institute for Cancer Research Princeton Branch , Princeton, NJ, USA
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9
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Han X, Qin H, Lu Y, Chen H, Yuan Z, Zhang Y, Yang X, Zheng L, Yan S. Post-translational modifications: The potential ways for killing cancer stem cells. Heliyon 2024; 10:e34015. [PMID: 39092260 PMCID: PMC11292267 DOI: 10.1016/j.heliyon.2024.e34015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 06/26/2024] [Accepted: 07/02/2024] [Indexed: 07/31/2024] Open
Abstract
While strides in cancer treatment continue to advance, the enduring challenges posed by cancer metastasis and recurrence persist as formidable contributors to the elevated mortality rates observed in cancer patients. Among the multifaceted factors implicated in tumor recurrence and metastasis, cancer stem cells (CSCs) emerge as noteworthy entities due to their inherent resistance to conventional therapies and heightened invasive capacities. Characterized by their notable abilities for self-renewal, differentiation, and initiation of tumorigenesis, the eradication of CSCs emerges as a paramount objective. Recent investigations increasingly emphasize the pivotal role of post-translational protein modifications (PTMs) in governing the self-renewal and replication capabilities of CSCs. This review accentuates the critical significance of several prevalent PTMs and the intricate interplay of PTM crosstalk in regulating CSC behavior. Furthermore, it posits that the manipulation of PTMs may offer a novel avenue for targeting and eliminating CSC populations, presenting a compelling perspective on cancer therapeutics with substantial potential for future applications.
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Affiliation(s)
- Xuedan Han
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China
| | - Hai Qin
- Department of Clinical Laboratory, Beijing Jishuitan Hospital Guizhou Hospital, No. 206, Sixian Street, Baiyun District, Guiyang City, 550014, Guizhou Province, China
| | - Yu Lu
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China
| | - Haitao Chen
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China
| | - Zhengdong Yuan
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China
| | - Yiwen Zhang
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China
| | - Xuena Yang
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China
| | - Lufeng Zheng
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China
| | - Simin Yan
- Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
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Shi Q, Xue C, Zeng Y, Yuan X, Chu Q, Jiang S, Wang J, Zhang Y, Zhu D, Li L. Notch signaling pathway in cancer: from mechanistic insights to targeted therapies. Signal Transduct Target Ther 2024; 9:128. [PMID: 38797752 PMCID: PMC11128457 DOI: 10.1038/s41392-024-01828-x] [Citation(s) in RCA: 86] [Impact Index Per Article: 86.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/31/2024] [Accepted: 04/15/2024] [Indexed: 05/29/2024] Open
Abstract
Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The Notch receptor and its ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical Notch signaling transduction. Accumulating evidence indicates that the Notch signaling pathway serves as both an oncogenic factor and a tumor suppressor in various cancer types. Dysregulation of this pathway promotes epithelial-mesenchymal transition and angiogenesis in malignancies, closely linked to cancer proliferation, invasion, and metastasis. Furthermore, the Notch signaling pathway contributes to maintaining stem-like properties in cancer cells, thereby enhancing cancer invasiveness. The regulatory role of the Notch signaling pathway in cancer metabolic reprogramming and the tumor microenvironment suggests its pivotal involvement in balancing oncogenic and tumor suppressive effects. Moreover, the Notch signaling pathway is implicated in conferring chemoresistance to tumor cells. Therefore, a comprehensive understanding of these biological processes is crucial for developing innovative therapeutic strategies targeting Notch signaling. This review focuses on the research progress of the Notch signaling pathway in cancers, providing in-depth insights into the potential mechanisms of Notch signaling regulation in the occurrence and progression of cancer. Additionally, the review summarizes pharmaceutical clinical trials targeting Notch signaling for cancer therapy, aiming to offer new insights into therapeutic strategies for human malignancies.
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Affiliation(s)
- Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Shuwen Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Jinzhi Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yaqi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Danhua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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11
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Duan X, Hu H, Wang L, Chen L. Aldehyde dehydrogenase 1 family: A potential molecule target for diseases. Cell Biol Int 2024. [PMID: 38800962 DOI: 10.1002/cbin.12188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 04/22/2024] [Accepted: 05/04/2024] [Indexed: 05/29/2024]
Abstract
Aldehyde dehydrogenase 1 (ALDH1), a crucial aldehyde metabolizing enzyme, has six family members. The ALDH1 family is expressed in various tissues, with a significant presence in the liver. It plays a momentous role in several pathophysiological processes, including aldehyde detoxification, oxidative stress, and lipid peroxidation. Acetaldehyde detoxification is the fundamental function of the ALDH1 family in participating in vital pathological mechanisms. The ALDH1 family can catalyze retinal to retinoic acid (RA) that is a hormone-signaling molecule and plays a vital role in the development and adult tissues. Furthermore, there is a need for further and broader research on the role of the ALDH1 family as a signaling molecule. The ALDH1 family is widely recognized as a cancer stem cell (CSC) marker and plays a significant role in the proliferation, invasion, metastasis, prognosis, and drug resistance of cancer. The ALDH1 family also participates in other human diseases, such as neurodegenerative diseases, osteoarthritis, diabetes, and atherosclerosis. It can inhibit disease progression by inhibiting/promoting the expression/activity of the ALDH1 family. In this review, we comprehensively analyze the tissue distribution, and functions of the ALDH1 family. Additionally, we review the involvement of the ALDH1 family in diseases, focusing on the underlying pathological mechanisms and briefly talk about the current status and development of ALDH1 family inhibitors. The ALDH1 family presents new possibilities for treating diseases, with both its upstream and downstream pathways serving as promising targets for therapeutic intervention. This offers fresh perspectives for drug development in the field of disease research.
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Affiliation(s)
- Xiangning Duan
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan, China
| | - Haoliang Hu
- Changde Research Centre for Artificial Intelligence and Biomedicine, Zoology Key Laboratory of Hunan Higher Education, College of Life and Environmental Sciences, Hunan University of Arts and Science, Changde, Hunan, China
| | - Lingzhi Wang
- Department of Pharmacy, The First Affiliated Hospital of Jishou University, Jishou, Hunan, China
| | - Linxi Chen
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan, China
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12
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Sipos F, Műzes G. Sirtuins Affect Cancer Stem Cells via Epigenetic Regulation of Autophagy. Biomedicines 2024; 12:386. [PMID: 38397988 PMCID: PMC10886574 DOI: 10.3390/biomedicines12020386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/01/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Sirtuins (SIRTs) are stress-responsive proteins that regulate several post-translational modifications, partly by acetylation, deacetylation, and affecting DNA methylation. As a result, they significantly regulate several cellular processes. In essence, they prolong lifespan and control the occurrence of spontaneous tumor growth. Members of the SIRT family have the ability to govern embryonic, hematopoietic, and other adult stem cells in certain tissues and cell types in distinct ways. Likewise, they can have both pro-tumor and anti-tumor effects on cancer stem cells, contingent upon the specific tissue from which they originate. The impact of autophagy on cancer stem cells, which varies depending on the specific circumstances, is a very intricate phenomenon that has significant significance for clinical and therapeutic purposes. SIRTs exert an impact on the autophagy process, whereas autophagy reciprocally affects the activity of certain SIRTs. The mechanism behind this connection in cancer stem cells remains poorly understood. This review presents the latest findings that position SIRTs at the point where cancer cells and autophagy interact. Our objective is to highlight the various roles of distinct SIRTs in cancer stem cell-related functions through autophagy. This would demonstrate their significance in the genesis and recurrence of cancer and offer a more precise understanding of their treatment possibilities in relation to autophagy.
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Affiliation(s)
- Ferenc Sipos
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary;
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Kaya SG, Eren G. Selective inhibition of SIRT2: A disputable therapeutic approach in cancer therapy. Bioorg Chem 2024; 143:107038. [PMID: 38113655 DOI: 10.1016/j.bioorg.2023.107038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 11/23/2023] [Accepted: 12/15/2023] [Indexed: 12/21/2023]
Abstract
Sirtuin 2 (SIRT2) is involved in a wide range of processes, from transcription to metabolism to genome stability. Dysregulation of SIRT2 has been associated with the pathogenesis and progression of different diseases, such as cancer and neurodegenerative disorders. In this context, targeting SIRT2 activity by small molecule inhibitors is a promising therapeutic strategy for treating related conditions, particularly cancer. This review summarizes the regulatory roles and molecular mechanisms of SIRT2 in cancer and the attempts to evaluate potential antitumor activities of SIRT2-selective inhibitors by in vitro and in vivo testing, which are expected to deepen our understanding of the role of SIRT2 in tumorigenesis and progression and may offer important clues or inspiration ideas for developing SIRT2 inhibitors with excellent affinity and selectivity.
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Affiliation(s)
- Selen Gozde Kaya
- SIRTeam Group, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Türkiye.
| | - Gokcen Eren
- SIRTeam Group, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Türkiye.
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14
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Zhu X, Yu J, Ai F, Wang Y, Lv W, Yu G, Cao X, Lin J. CD24 May Serve as an Immunotherapy Target in Triple-Negative Breast Cancer by Regulating the Expression of PD-L1. BREAST CANCER (DOVE MEDICAL PRESS) 2023; 15:967-984. [PMID: 38164371 PMCID: PMC10758189 DOI: 10.2147/bctt.s409054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024]
Abstract
PURPOSE CD24 mediates a "don't eat me" signal to escape the immune environment. However, the correlation between CD24 and PD-L1 is unclear. This study aimed to assess if CD24 can serve as a target for immunotherapy of triple-negative breast cancer (TNBC). METHODS Data on CD24 expression in breast cancer were acquired using the Oncomine and UALCAN tools. The role of CD24 expression on the prognosis of patients with TNBC was assessed using Kaplan-Meier analyses. Subsequently, STRING and TISIDB databases were used to construct protein-protein interaction networks and to explore immune-related molecules regulated by CD24. Immunofluorescence and immunohistochemistry assays were conducted to validate CD24 and PD-L1 expression and tumor infiltration lymphocyte (TIL) level. Survival analysis was also performed to explore the effect of CD24 and PD-L1 expression and TIL level in patients with TNBC. ShRNA was also used to explore the regulation role of CD24 on PD-L1 expression. RESULTS CD24 expression was significantly higher in breast cancer than in normal tissues, with high expression being significantly associated with a worse prognosis. CD24 was found to be significantly regulated by chemokines, immunoinhibitors, immunostimulators and TILs. Furthermore, CD24 expression showed a significant positive correlation with PD-L1 expression and a negative correlation with TIL level. In association with PD-L1, CD24 was found to positively regulate lymphocyte costimulation, T cell costimulation, and leukocyte activation. Furthermore, CD24 and PD-L1 co-expression contributed to worse survival outcomes. In addition, CD24 expression was found to attenuate the positive effects of high-level TILs on the prognosis of patients with TNBC. CD24 can also regulate the expression of PD-L1 in TNBC cells. CONCLUSION CD24 may attenuate the positive effects of high TIL levels on survival and may facilitate the immune escape of TNBC by regulating PD-L1 expression. Thus, it is a potential target for immunotherapy in TNBC.
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Affiliation(s)
- Xudong Zhu
- Department of General Surgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, 110042, People’s Republic of China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People’s Republic of China
| | - Jiahui Yu
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People’s Republic of China
| | - Fulu Ai
- Department of General Surgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, 110042, People’s Republic of China
| | - Yue Wang
- Department of General Surgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, 110042, People’s Republic of China
| | - Wu Lv
- Department of General Surgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, 110042, People’s Republic of China
| | - Guilin Yu
- Department of General Surgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, 110042, People’s Republic of China
| | - Xiankui Cao
- Department of General Surgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, 110042, People’s Republic of China
| | - Jie Lin
- Department of General Surgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, 110042, People’s Republic of China
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Duan JJ, Cai J, Gao L, Yu SC. ALDEFLUOR activity, ALDH isoforms, and their clinical significance in cancers. J Enzyme Inhib Med Chem 2023; 38:2166035. [PMID: 36651035 PMCID: PMC9858439 DOI: 10.1080/14756366.2023.2166035] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
High aldehyde dehydrogenase (ALDH) activity is a metabolic feature of adult stem cells and various cancer stem cells (CSCs). The ALDEFLUOR system is currently the most commonly used method for evaluating ALDH enzyme activity in viable cells. This system is applied extensively in the isolation of normal stem cells and CSCs from heterogeneous cell populations. For many years, ALDH1A1 has been considered the most important subtype among the 19 ALDH family members in determining ALDEFLUOR activity. However, in recent years, studies of many types of normal and tumour tissues have demonstrated that other ALDH subtypes can also significantly influence ALDEFLUOR activity. In this article, we briefly review the relationships between various members of the ALDH family and ALDEFLUOR activity. The clinical significance of these ALDH isoforms in different cancers and possible directions for future studies are also summarised.
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Affiliation(s)
- Jiang-Jie Duan
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital; Third Military Medical University (Army Medical University), Chongqing, China,International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Chongqing, China,Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Chongqing, China,Ministry of Education, Key Laboratory of Cancer Immunopathology, Chongqing, China
| | - Jiao Cai
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital; Third Military Medical University (Army Medical University), Chongqing, China,International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Chongqing, China,Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Chongqing, China,Ministry of Education, Key Laboratory of Cancer Immunopathology, Chongqing, China
| | - Lei Gao
- Department of Hematology, Xinqiao Hospital; Third Medical University (Army Medical University), Chongqing, China
| | - Shi-Cang Yu
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital; Third Military Medical University (Army Medical University), Chongqing, China,International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Chongqing, China,Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Chongqing, China,Ministry of Education, Key Laboratory of Cancer Immunopathology, Chongqing, China,Jin-feng Laboratory, Chongqing, China,CONTACT Shi-Cang Yu Department of Stem Cell and Regenerative Medicine, Third Military Medical University (Army Medical University), Chongqing400038, China
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Jan N, Sofi S, Qayoom H, Haq BU, Shabir A, Mir MA. Targeting breast cancer stem cells through retinoids: A new hope for treatment. Crit Rev Oncol Hematol 2023; 192:104156. [PMID: 37827439 DOI: 10.1016/j.critrevonc.2023.104156] [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: 06/04/2023] [Revised: 09/09/2023] [Accepted: 10/06/2023] [Indexed: 10/14/2023] Open
Abstract
Breast cancer is a complex and diverse disease accounting for nearly 30% of all cancers diagnosed in females. But unfortunately, patients develop resistance to the existing chemotherapeutic regimen, resulting in approximately 90% treatment failure. With over half a million deaths annually, it is imperative to explore new therapeutic approaches to combat the disease. Within a breast tumor, a small sub-population of heterogeneous cells, with a unique ability of self-renew and differentiation and responsible for tumor formation, initiation, and recurrence are referred to as breast cancer stem cells (BCSCs). These BCSCs have been identified as one of the main contributors to chemoresistance in breast cancer, making them an attractive target for developing novel therapeutic strategies. These cells exhibit surface biomarkers such as CD44+, CD24-/LOW, ALDH, CD133, and CD49f phenotypes. Higher expression of CD44+ and ALDH activity has been associated with the formation of tumors in various cancers. Moreover, the abnormal regulation of signaling pathways, including Hedgehog, Notch, β-catenin, JAK/STAT, and P13K/AKT/mTOR, leads to the formation of cancer stem cells, resulting in the development of tumors. The growing drug resistance in BC is a significant challenge, highlighting the need for new therapeutic strategies to combat this dreadful disease. Retinoids, a large group of synthetic derivatives of vitamin A, have been studied as chemopreventive agents in clinical trials and have been shown to regulate various crucial biological functions including vision, development, inflammation, and metabolism. On a cellular level, the retinoid activity has been well characterized and translated and is known to induce differentiation and apoptosis, which play important roles in the outcome of the transformation of tissues into malignant. Retinoids have been investigated extensively for their use in the treatment and prevention of cancer due to their high receptor-binding affinity to directly modulate gene expression programs. Therefore, in this study, we aim to summarize the current understanding of BCSCs, their biomarkers, and the associated signaling pathways. Retinoids, such as Adapalene, a third-generation retinoid, have shown promising anti-cancer potential and may serve as therapeutic agents to target BCSCs.
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Affiliation(s)
- Nusrat Jan
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Shazia Sofi
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Hina Qayoom
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Burhan Ul Haq
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Aisha Shabir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Manzoor Ahmad Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India.
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Zhang Z, Wang Y, Liang Z, Meng Z, Zhang X, Ma G, Chen Y, Zhang M, Su Y, Li Z, Liang Y, Niu H. Modification of lysine-260 2-hydroxyisobutyrylation destabilizes ALDH1A1 expression to regulate bladder cancer progression. iScience 2023; 26:108142. [PMID: 37867947 PMCID: PMC10585400 DOI: 10.1016/j.isci.2023.108142] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/11/2023] [Accepted: 10/02/2023] [Indexed: 10/24/2023] Open
Abstract
ALDH1A1 is one of the classical stem cell markers for bladder cancer. Lysine 2-hydroxyisobutyrylation (Khib) is a newfound modification to modulate the protein expression, and the underlying mechanisms of how ALDH1A1 was regulated by Khib modification in bladder cancer remains unknown. Here, ALDH1A1 showed a decreased K260hib modification, as identified by protein modification omics in bladder cancer. Decreasing ALDH1A1 expression significantly suppressed the proliferation, migration and invasion of bladder cancer cells. Moreover, K260hib modification is responsible for the activity of ALDH1A1 in bladder cancer, which is regulated by HDAC2/3. Higher K260hib modification on ALDH1A1 promotes protein degradation through chaperone-mediated autophagy (CMA), and ALDH1A1 K260hib could sensitize bladder cancer cells to chemotherapeutic drugs. Higher ALDH1A1 expression with a lower K260hib modification indicates a poor prognosis in patients with bladder cancer. Overall, we demonstrated that K260hib of ALDH1A1 can be used as a potential therapeutic target for bladder cancer treatment.
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Affiliation(s)
- Zhilei Zhang
- Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Yonghua Wang
- Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
| | - Zhijuan Liang
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Zhaoyuan Meng
- School of Basic Medicine, Qingdao University, No.308 Ningxia Road, Qingdao 266071, China
| | - Xiangyan Zhang
- Department of Pathology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
| | - Guofeng Ma
- Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Yuanbin Chen
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Mingxin Zhang
- Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
| | - Yinjie Su
- Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Zhiqiang Li
- The Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao 266071, China
| | - Ye Liang
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Haitao Niu
- Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
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18
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Ding B, Song Y, Liu S, Peng C, Zhang Y. Mechanisms underlying the changes in acetaldehyde dehydrogenase 1 in cholangiocarcinoma. J Cancer 2023; 14:3203-3213. [PMID: 37928420 PMCID: PMC10622993 DOI: 10.7150/jca.86967] [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: 06/09/2023] [Accepted: 09/08/2023] [Indexed: 11/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the most recurrent malignant tumor found in the biliary system. It originates from the bile duct epithelial cells characterized by easy metastasis, high intermittent rate, and poor prognosis. Acetaldehyde dehydrogenase 1 (ALDH1), a marker of cancer stem cells, the levels of which are particularly elevated in various of malignant tumors. Additionally, the increased ALDH1 levels are closely related to the degree and prognosis of malignant tumors. This study reviewed the mechanisms underlying the changes in ALDH1 levels in CCA.
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Affiliation(s)
- Bai Ding
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005 Hunan Province, China
| | - Yinghui Song
- Central Laboratory of Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410015, China
| | - Sulai Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005 Hunan Province, China
- Central Laboratory of Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410015, China
| | - Chuang Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005 Hunan Province, China
| | - Yujing Zhang
- Central Laboratory of Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410015, China
- Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
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Xanthis V, Mantso T, Dimtsi A, Pappa A, Fadouloglou VE. Human Aldehyde Dehydrogenases: A Superfamily of Similar Yet Different Proteins Highly Related to Cancer. Cancers (Basel) 2023; 15:4419. [PMID: 37686694 PMCID: PMC10650815 DOI: 10.3390/cancers15174419] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/30/2023] [Accepted: 09/01/2023] [Indexed: 09/10/2023] Open
Abstract
The superfamily of human aldehyde dehydrogenases (hALDHs) consists of 19 isoenzymes which are critical for several physiological and biosynthetic processes and play a major role in the organism's detoxification via the NAD(P) dependent oxidation of numerous endogenous and exogenous aldehyde substrates to their corresponding carboxylic acids. Over the last decades, ALDHs have been the subject of several studies as it was revealed that their differential expression patterns in various cancer types are associated either with carcinogenesis or promotion of cell survival. Here, we attempt to provide a thorough review of hALDHs' diverse functions and 3D structures with particular emphasis on their role in cancer pathology and resistance to chemotherapy. We are especially interested in findings regarding the association of structural features and their changes with effects on enzymes' functionalities. Moreover, we provide an updated outline of the hALDHs inhibitors utilized in experimental or clinical settings for cancer therapy. Overall, this review aims to provide a better understanding of the impact of ALDHs in cancer pathology and therapy from a structural perspective.
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Affiliation(s)
| | | | | | | | - Vasiliki E. Fadouloglou
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
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O'Brien C, Ling T, Berman JM, Culp-Hill R, Reisz JA, Rondeau V, Jahangiri S, St-Germain J, Macwan V, Astori A, Zeng A, Hong JY, Li M, Yang M, Jana S, Gamboni F, Tsao E, Liu W, Dick JE, Lin H, Melnick A, Tikhonova A, Arruda A, Minden MD, Raught B, D'Alessandro A, Jones CL. Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity. Haematologica 2023; 108:2343-2357. [PMID: 37021547 PMCID: PMC10483359 DOI: 10.3324/haematol.2022.281894] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 03/30/2023] [Indexed: 04/07/2023] Open
Abstract
Outcomes for patients with acute myeloid leukemia (AML) remain poor due to the inability of current therapeutic regimens to fully eradicate disease-initiating leukemia stem cells (LSC). Previous studies have demonstrated that oxidative phosphorylation (OXPHOS) is an essential process that is targetable in LSC. Sirtuin 3 (SIRT3), a mitochondrial deacetylase with a multi-faceted role in metabolic regulation, has been shown to regulate OXPHOS in cancer models; however, it has not yet been studied in the context of LSC. Thus, we sought to identify if SIRT3 is important for LSC function. Using RNAi and a SIRT3 inhibitor (YC8-02), we demonstrate that SIRT3 is a critical target for the survival of primary human LSC but is not essential for normal human hematopoietic stem and progenitor cell function. In order to elucidate the molecular mechanisms by which SIRT3 is essential in LSC we combined transcriptomic, proteomic, and lipidomic approaches, showing that SIRT3 is important for LSC function through the regulation of fatty acid oxidation (FAO) which is required to support OXPHOS and ATP production in human LSC. Further, we discovered two approaches to further sensitize LSC to SIRT3 inhibition. First, we found that LSC tolerate the toxic effects of fatty acid accumulation induced by SIRT3 inhibition by upregulating cholesterol esterification. Disruption of cholesterol homeostasis sensitizes LSC to YC8-02 and potentiates LSC death. Second, SIRT3 inhibition sensitizes LSC to the BCL-2 inhibitor venetoclax. Together, these findings establish SIRT3 as a regulator of lipid metabolism and potential therapeutic target in primitive AML cells.
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Affiliation(s)
- Cristiana O'Brien
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Tianyi Ling
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Jacob M Berman
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Rachel Culp-Hill
- Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Julie A Reisz
- Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Vincent Rondeau
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Soheil Jahangiri
- Department of Medical Biophysics, University of Toronto, Toronto, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | | | - Vinitha Macwan
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Audrey Astori
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Andy Zeng
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Jun Young Hong
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Meng Li
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Min Yang
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Sadhan Jana
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Fabia Gamboni
- Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Emily Tsao
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Weiyi Liu
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - John E Dick
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Hening Lin
- Howard Hughes Medical Institute; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Ari Melnick
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Anastasia Tikhonova
- Department of Medical Biophysics, University of Toronto, Toronto, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Andrea Arruda
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Mark D Minden
- Department of Medical Biophysics, University of Toronto, Toronto, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Brian Raught
- Department of Medical Biophysics, University of Toronto, Toronto, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Angelo D'Alessandro
- Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Courtney L Jones
- Department of Medical Biophysics, University of Toronto, Toronto, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
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Fu G, Li ST, Jiang Z, Mao Q, Xiong N, Li X, Hao Y, Zhang H. PGAM5 deacetylation mediated by SIRT2 facilitates lipid metabolism and liver cancer proliferation. Acta Biochim Biophys Sin (Shanghai) 2023; 55:1370-1379. [PMID: 37580952 PMCID: PMC10520483 DOI: 10.3724/abbs.2023155] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 02/13/2023] [Indexed: 08/16/2023] Open
Abstract
Tumor metabolic reprogramming and epigenetic modification work together to promote tumorigenesis and development. Protein lysine acetylation, which affects a variety of biological functions of proteins, plays an important role under physiological and pathological conditions. Here, through immunoprecipitation and mass spectrum data, we show that phosphoglycerate mutase 5 (PGAM5) deacetylation enhances malic enzyme 1 (ME1) metabolic enzyme activity to promote lipid synthesis and proliferation of liver cancer cells. Mechanistically, we demonstrate that the deacetylase SIRT2 mediates PGAM5 deacetylation to activate ME1 activity, leading to ME1 dephosphorylation, subsequent lipid accumulation and the proliferation of liver cancer cells. Taken together, our study establishes an important role for the SIRT2-PGAM5-ME1 axis in the proliferation of liver cancer cells, suggesting a potential innovative cancer therapy.
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Affiliation(s)
- Gongyu Fu
- Anhui Key Laboratory of Hepatopancreatobiliary SurgeryDepartment of General SurgeryAnhui Provincial Hospitalthe First Affiliated Hospital of USTCDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
- Hefei National Laboratory for Physical Sciences at Microscalethe Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
| | - Shi-Ting Li
- Guangdong Cardiovascular InstituteGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China
| | - Zetan Jiang
- Anhui Key Laboratory of Hepatopancreatobiliary SurgeryDepartment of General SurgeryAnhui Provincial Hospitalthe First Affiliated Hospital of USTCDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
- Hefei National Laboratory for Physical Sciences at Microscalethe Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
| | - Qiankun Mao
- Anhui Key Laboratory of Hepatopancreatobiliary SurgeryDepartment of General SurgeryAnhui Provincial Hospitalthe First Affiliated Hospital of USTCDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
- Hefei National Laboratory for Physical Sciences at Microscalethe Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
| | - Nanchi Xiong
- Anhui Key Laboratory of Hepatopancreatobiliary SurgeryDepartment of General SurgeryAnhui Provincial Hospitalthe First Affiliated Hospital of USTCDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
- Hefei National Laboratory for Physical Sciences at Microscalethe Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
| | - Xiang Li
- Hefei National Laboratory for Physical Sciences at Microscalethe Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
| | - Yijie Hao
- Anhui Key Laboratory of Hepatopancreatobiliary SurgeryDepartment of General SurgeryAnhui Provincial Hospitalthe First Affiliated Hospital of USTCDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
- Hefei National Laboratory for Physical Sciences at Microscalethe Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
| | - Huafeng Zhang
- Anhui Key Laboratory of Hepatopancreatobiliary SurgeryDepartment of General SurgeryAnhui Provincial Hospitalthe First Affiliated Hospital of USTCDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
- Hefei National Laboratory for Physical Sciences at Microscalethe Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
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22
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Ordaz-Ramos A, Tellez-Jimenez O, Vazquez-Santillan K. Signaling pathways governing the maintenance of breast cancer stem cells and their therapeutic implications. Front Cell Dev Biol 2023; 11:1221175. [PMID: 37492224 PMCID: PMC10363614 DOI: 10.3389/fcell.2023.1221175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 06/28/2023] [Indexed: 07/27/2023] Open
Abstract
Breast cancer stem cells (BCSCs) represent a distinct subpopulation of cells with the ability to self-renewal and differentiate into phenotypically diverse tumor cells. The involvement of CSC in treatment resistance and cancer recurrence has been well established. Numerous studies have provided compelling evidence that the self-renewal ability of cancer stem cells is tightly regulated by specific signaling pathways, which exert critical roles to maintain an undifferentiated phenotype and prevent the differentiation of CSCs. Signaling pathways such as Wnt/β-catenin, NF-κB, Notch, Hedgehog, TGF-β, and Hippo have been implicated in the promotion of self-renewal of many normal and cancer stem cells. Given the pivotal role of BCSCs in driving breast cancer aggressiveness, targeting self-renewal signaling pathways holds promise as a viable therapeutic strategy for combating this disease. In this review, we will discuss the main signaling pathways involved in the maintenance of the self-renewal ability of BCSC, while also highlighting current strategies employed to disrupt the signaling molecules associated with stemness.
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Affiliation(s)
- Alejandro Ordaz-Ramos
- Innovation in Precision Medicine Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, México
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Circuito de Posgrados, Ciudad Universitaria, Coyoacán, México
| | - Olivia Tellez-Jimenez
- Innovation in Precision Medicine Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, México
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Circuito de Posgrados, Ciudad Universitaria, Coyoacán, México
| | - Karla Vazquez-Santillan
- Innovation in Precision Medicine Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, México
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23
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Minic Z, Li Y, Hüttmann N, Uppal GK, D’Mello R, Berezovski MV. Lysine Acetylome of Breast Cancer-Derived Small Extracellular Vesicles Reveals Specific Acetylation Patterns for Metabolic Enzymes. Biomedicines 2023; 11:biomedicines11041076. [PMID: 37189694 DOI: 10.3390/biomedicines11041076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 03/20/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Cancer-derived small extracellular vesicles have been proposed as promising potential biomarkers for diagnosis and prognosis of breast cancer (BC). We performed a proteomic study of lysine acetylation of breast cancer-derived small extracellular vesicles (sEVs) to understand the potential role of the aberrant acetylated proteins in the biology of invasive ductal carcinoma and triple-negative BC. Three cell lines were used as models for this study: MCF10A (non-metastatic), MCF7 (estrogen and progesterone receptor-positive, metastatic) and MDA-MB-231 (triple-negative, highly metastatic). For a comprehensive protein acetylation analysis of the sEVs derived from each cell line, acetylated peptides were enriched using the anti-acetyl-lysine antibody, followed by LC-MS/MS analysis. In total, there were 118 lysine-acetylated peptides, of which 22, 58 and 82 have been identified in MCF10A, MCF7 and MDA-MB-231 cell lines, respectively. These acetylated peptides were mapped to 60 distinct proteins and mainly identified proteins involved in metabolic pathways. Among the acetylated proteins identified in cancer-derived sEVs from MCF7 and MDA-MB-231 cell lines are proteins associated with the glycolysis pathway, annexins and histones. Five acetylated enzymes from the glycolytic pathway, present only in cancer-derived sEVs, were validated. These include aldolase (ALDOA), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK1), enolase (ENO) and pyruvate kinase M1/2 (PKM). For three of these enzymes (ALDOA, PGK1 and ENO) the specific enzymatic activity was significantly higher in MDA-MB-231 when compared with MCF10A-derived sEVs. This study reveals that sEVs contain acetylated glycolytic metabolic enzymes that could be interesting potential candidates for early BC diagnostics.
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Affiliation(s)
- Zoran Minic
- John L. Holmes Mass Spectrometry Facility, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Yingxi Li
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Nico Hüttmann
- John L. Holmes Mass Spectrometry Facility, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Gurcharan K. Uppal
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Rochelle D’Mello
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Maxim V. Berezovski
- John L. Holmes Mass Spectrometry Facility, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, Canada
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada
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24
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Mehdipour M, Park S, Huang GN. Unlocking cardiomyocyte renewal potential for myocardial regeneration therapy. J Mol Cell Cardiol 2023; 177:9-20. [PMID: 36801396 PMCID: PMC10699255 DOI: 10.1016/j.yjmcc.2023.02.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/28/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023]
Abstract
Cardiovascular disease remains the leading cause of mortality worldwide. Cardiomyocytes are irreversibly lost due to cardiac ischemia secondary to disease. This leads to increased cardiac fibrosis, poor contractility, cardiac hypertrophy, and subsequent life-threatening heart failure. Adult mammalian hearts exhibit notoriously low regenerative potential, further compounding the calamities described above. Neonatal mammalian hearts, on the other hand, display robust regenerative capacities. Lower vertebrates such as zebrafish and salamanders retain the ability to replenish lost cardiomyocytes throughout life. It is critical to understand the varying mechanisms that are responsible for these differences in cardiac regeneration across phylogeny and ontogeny. Adult mammalian cardiomyocyte cell cycle arrest and polyploidization have been proposed as major barriers to heart regeneration. Here we review current models about why adult mammalian cardiac regenerative potential is lost including changes in environmental oxygen levels, acquisition of endothermy, complex immune system development, and possible cancer risk tradeoffs. We also discuss recent progress and highlight conflicting reports pertaining to extrinsic and intrinsic signaling pathways that control cardiomyocyte proliferation and polyploidization in growth and regeneration. Uncovering the physiological brakes of cardiac regeneration could illuminate novel molecular targets and offer promising therapeutic strategies to treat heart failure.
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Affiliation(s)
- Melod Mehdipour
- Cardiovascular Research Institute and Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94158, USA; Bakar Aging Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Sangsoon Park
- Cardiovascular Research Institute and Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94158, USA; Bakar Aging Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Guo N Huang
- Cardiovascular Research Institute and Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94158, USA; Bakar Aging Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
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25
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1'-O-methyl-averantin isolated from the endolichenic fungus Jackrogersella sp. EL001672 suppresses colorectal cancer stemness via sonic Hedgehog and Notch signaling. Sci Rep 2023; 13:2811. [PMID: 36797277 PMCID: PMC9935543 DOI: 10.1038/s41598-023-28773-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 01/24/2023] [Indexed: 02/18/2023] Open
Abstract
Endolichenic fungi are host organisms that live on lichens and produce a wide variety of secondary metabolites. Colorectal cancer stem cells are capable of self-renewal and differentiation into cancer cells, which makes cancers difficult to eradicate. New alternative therapeutics are needed to inhibit the growth of tumor stem cells. This study examined the ability of an extract of Jackrogersella sp. EL001672 (derived from the lichen Cetraria sp.) and the isolated compound 1'-O-methyl-averantin to inhibit development of cancer stemness. The endolichenic fungus Jackrogersella sp. EL001672 (KACC 83021BP), derived from Cetraria sp., was grown in culture medium. The culture broth was extracted with acetone to obtain a crude extract. Column chromatography and reverse-phase HPLC were used to isolate an active compound. The anticancer activity of the extract and the isolated compound was evaluated by qRT-PCR and western blotting, and in cell viability, spheroid formation, and reporter assays. The acetone extract of EL001672 did not affect cell viability. However, 1'-O-methyl-averantin showed cytotoxic effects against cancer cell lines at 50 μg/mL and 25 μg/mL. Both the crude extract and 1'-O-methyl-averantin suppressed spheroid formation in CRC cell lines, and downregulated expression of stemness markers ALDH1, CD44, CD133, Lgr-5, Msi-1, and EphB1. To further characterize the mechanism underlying anti-stemness activity, we examined sonic Hedgehog and Notch signaling. The results showed that the crude extract and the 1'-O-methyl-averantin inhibited Gli1, Gli2, SMO, Bmi-1, Notch-1, Hes-1, and the CSL complex. Consequently, an acetone extract and 1'-O-methyl-averantin isolated from EL001672 suppresses colorectal cancer stemness by regulating the sonic Hedgehog and Notch signaling pathways.
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26
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In silico drug discovery of SIRT2 inhibitors from natural source as anticancer agents. Sci Rep 2023; 13:2146. [PMID: 36750593 PMCID: PMC9905574 DOI: 10.1038/s41598-023-28226-7] [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: 09/04/2022] [Accepted: 01/16/2023] [Indexed: 02/09/2023] Open
Abstract
Sirtuin 2 (SIRT2) is a member of the sirtuin protein family, which includes lysine deacylases that are NAD+-dependent and organize several biological processes. Different forms of cancer have been associated with dysregulation of SIRT2 activity. Hence, identifying potent inhibitors for SIRT2 has piqued considerable attention in the drug discovery community. In the current study, the Natural Products Atlas (NPAtlas) database was mined to hunt potential SIRT2 inhibitors utilizing in silico techniques. Initially, the performance of the employed docking protocol to anticipate ligand-SIRT2 binding mode was assessed according to the accessible experimental data. Based on the predicted docking scores, the most promising NPAtlas molecules were selected and submitted to molecular dynamics (MD) simulations, followed by binding energy computations. Based on the MM-GBSA binding energy estimations over a 200 ns MD course, three NPAtlas compounds, namely NPA009578, NPA006805, and NPA001884, were identified with better ΔGbinding towards SIRT2 protein than the native ligand (SirReal2) with values of - 59.9, - 57.4, - 53.5, and - 49.7 kcal/mol, respectively. On the basis of structural and energetic assessments, the identified NPAtlas compounds were confirmed to be steady over a 200 ns MD course. The drug-likeness and pharmacokinetic characteristics of the identified NPAtlas molecules were anticipated, and robust bioavailability was predicted. Conclusively, the current results propose potent inhibitors for SIRT2 deserving more in vitro/in vivo investigation.
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27
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Wang L, Cao G, Li W, Chen XW, Xiong SS, Mu YN, Jiang JF, Yang L, Zhang DR, Cao YW. Expressions and Prognostic Values of Notch3 and DLL4 in Human Breast Cancer. Technol Cancer Res Treat 2023; 22:15330338221118984. [PMID: 36740988 PMCID: PMC9903027 DOI: 10.1177/15330338221118984] [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] [Indexed: 02/07/2023] Open
Abstract
Background: Notch signaling played a critical role in promoting breast tumorigenesis and progression. However, the role and prognostic value of Notch3 combined with DLL4 expression in breast carcinoma had not been explored. Methods: The retrospective study enrolled 90 breast cancer tissues and 60 noncancerous tissues from (conceal). The expression and prognostic value of Notch3 and DLL4 in patients with breast carcinoma were investigated using Oncomine and UALCAN database. Notch3 and DLL4 expression levels were detected by quantitative real-time polymerase chain reaction, western blotting, and immunohistochemistry. We analyzed the correlation between both proteins expression and clinicopathological parameters and survival data, respectively. Results: The expressions of Notch3 and DLL4 were increased, and Notch3 expression was significantly positively associated with DLL4 in breast carcinoma. The 2 proteins dramatically correlated with advanced stage, high grade and negative Her2 status. The overexpressing of single or both Notch3 and DLL4 resulted in shortened survival of breast cancer patients. And Notch3 overexpression was one of independent risk predictors to poor prognosis. Conclusion: The interaction of Notch3 receptor and DLL4 ligand accelerates oncogenesis, progression, and poor prognosis of breast cancer patients. Notch3 protein may serve as one of biomarker to independently predict prognosis of patients.
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Affiliation(s)
- Lin Wang
- Shihezi University School of Medicine, Shihezi, Xinjiang, China,Changle People's Hospital, Weifang, Shandong, China
| | - Ge Cao
- Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Wei Li
- Shandong Provincial Western Hospital, Jinan, , Shandong, China
| | - Xiao-Wen Chen
- Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | | | - Ya-Nan Mu
- Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Jin-Fang Jiang
- Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Lan Yang
- Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - De-Rui Zhang
- Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Yu-Wen Cao
- Shihezi University School of Medicine, Shihezi, Xinjiang, China,The First Affiliated Hospital of Shihezi University School of Medicine, Shihezi University School of Medicine, Shihezi, Xinjiang, China,Yu-Wen Cao, Department of Pathology, Shihezi University School of Medicine, Shihezi 832000, Xinjiang, China.
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28
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Guo XJ, Huang XY, Yang X, Lu JC, Wei CY, Gao C, Pei YZ, Chen Y, Sun QM, Cai JB, Zhou J, Fan J, Ke AW, Shi YG, Shen YH, Zhang PF, Shi GM, Yang GH. Loss of 5-hydroxymethylcytosine induces chemotherapy resistance in hepatocellular carcinoma via the 5-hmC/PCAF/AKT axis. Cell Death Dis 2023; 14:79. [PMID: 36732324 PMCID: PMC9895048 DOI: 10.1038/s41419-022-05406-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 11/03/2022] [Accepted: 11/04/2022] [Indexed: 02/04/2023]
Abstract
Multidrug resistance is a major challenge in treating advanced hepatocellular carcinoma (HCC). Although recent studies have reported that the multidrug resistance phenotype is associated with abnormal DNA methylation in cancer cells, the epigenetic mechanism underlying multidrug resistance remains unknown. Here, we reported that the level of 5-hydroxymethylcytosine (5-hmC) in human HCC tissues was significantly lower than that in adjacent liver tissues, and reduced 5-hmC significantly correlated with malignant phenotypes, including poor differentiation and microvascular invasion; additionally, loss of 5-hmC was related to chemotherapy resistance in post-transplantation HCC patients. Further, the 5-hmC level was regulated by ten-eleven translocation 2 (TET2), and the reduction of TET2 in HCC contributes to chemotherapy resistance through histone acetyltransferase P300/CBP-associated factor (PCAF) inhibition and AKT signaling hyperactivation. In conclusion, loss of 5-hmC induces chemotherapy resistance through PCAF/AKT axis and is a promising chemosensitivity prediction biomarker and therapeutic target for HCC patients.
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Affiliation(s)
- Xiao-Jun Guo
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China
| | - Xiao-Yong Huang
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China
| | - Xuan Yang
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China
- Department of General Surgery, Peking University Third Hospital, Beijing, PR China
| | - Jia-Cheng Lu
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China
| | - Chuan-Yuan Wei
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China
| | - Chao Gao
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China
| | - Yan-Zi Pei
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China
| | - Yi Chen
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China
| | - Qi-Man Sun
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China
| | - Jia-Bin Cai
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China
| | - Jian Zhou
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China
| | - Jia Fan
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China
| | - Ai-Wu Ke
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China
| | - Yujiang G Shi
- Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, PR China.
| | - Ying-Hao Shen
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China.
| | - Peng-Fei Zhang
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China.
- Department of Medical Oncology, Zhongshan Hospital of Fudan University, Shanghai, 200032, PR China.
- Cancer Center, Zhongshan Hospital of Fudan University, Shanghai, 200032, PR China.
| | - Guo-Ming Shi
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China.
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China.
- Clinical Research Unit, Institute of Clinical Science, Zhongshan Hospital of Fudan University, Shanghai, 200032, PR China.
| | - Guo-Huan Yang
- Department of Liver Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, PR China.
- Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, 200032, PR China.
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29
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Wang Y, Chen Y, Garcia-Milian R, Golla JP, Charkoftaki G, Lam TT, Thompson DC, Vasiliou V. Proteomic profiling reveals an association between ALDH and oxidative phosphorylation and DNA damage repair pathways in human colon adenocarcinoma stem cells. Chem Biol Interact 2022; 368:110175. [PMID: 36162455 PMCID: PMC9891852 DOI: 10.1016/j.cbi.2022.110175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 08/11/2022] [Accepted: 09/05/2022] [Indexed: 02/03/2023]
Abstract
Several members of the aldehyde dehydrogenase (ALDH) family, especially ALDH1 isoenzymes, have been identified as biomarkers of cancer stem cells (CSCs), a small subpopulation of oncogenic cells with self-renewal and multipotency capability. Consistent with this contention, cell populations with high ALDH enzymatic activity exhibit greater carcinogenic potential. It has been reported that ALDH1, especially ALDH1A1, serves as a valuable biomarker for colon CSCs. However, the functional roles of ALDHs in CSCs and solid tumors of the colon tissue is not fully understood. The aim of the present study was to identify molecular signature associated with high ALDH activity in human colorectal adenocarcinoma (COLO320DM) cells by proteomics profiling. Aldefluor™ assay was performed to sort COLO320DM cells exhibiting high (ALDHhigh) and low (ALDHlow) ALDH activity. Label-free quantitative proteomics analyses were conducted on these two cell populations. Proteomics profiling revealed a total of 229 differentially expressed proteins (DEPs) in ALDHhigh relative to ALDHlow cells, of which 182 were down-regulated and 47 were up-regulated. In agreement with previous studies, ALDH1A1 appeared to be the principal ALDH isozyme contributing to the Aldefluor™ assay activity in COLO320DM cells. Ingenuity pathway analysis of the proteomic datasets indicated that DEPs were associated with mitochondrial dysfunction, sirtuin signaling, oxidative phosphorylation and nucleotide excision repair. Our proteomics study predicts that high ALDH1A1 activity may be involved in these cellular pathways to promote a metabolic switch and cellular survival of CSCs.
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Affiliation(s)
- Yewei Wang
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Ying Chen
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Rolando Garcia-Milian
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA; Bioinformatics Support Program, Cushing/Whitney Medical Library, Yale University, New Haven, CT, USA
| | - Jaya Prakash Golla
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Georgia Charkoftaki
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - TuKiet T Lam
- Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA; Yale MS & Proteomics Resource, WM Keck Foundation Biotechnology Resource Laboratory, New Haven, CT, USA
| | - David C Thompson
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.
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30
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Liu J, Wang Q, Kang Y, Xu S, Pang D. Unconventional protein post-translational modifications: the helmsmen in breast cancer. Cell Biosci 2022; 12:22. [PMID: 35216622 PMCID: PMC8881842 DOI: 10.1186/s13578-022-00756-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 02/07/2022] [Indexed: 01/10/2023] Open
Abstract
AbstractBreast cancer is the most prevalent malignant tumor and a leading cause of mortality among females worldwide. The tumorigenesis and progression of breast cancer involve complex pathophysiological processes, which may be mediated by post-translational modifications (PTMs) of proteins, stimulated by various genes and signaling pathways. Studies into PTMs have long been dominated by the investigation of protein phosphorylation and histone epigenetic modifications. However, with great advances in proteomic techniques, several other PTMs, such as acetylation, glycosylation, sumoylation, methylation, ubiquitination, citrullination, and palmitoylation have been confirmed in breast cancer. Nevertheless, the mechanisms, effects, and inhibitors of these unconventional PTMs (particularly, the non-histone modifications other than phosphorylation) received comparatively little attention. Therefore, in this review, we illustrate the functions of these PTMs and highlight their impact on the oncogenesis and progression of breast cancer. Identification of novel potential therapeutic drugs targeting PTMs and development of biological markers for the detection of breast cancer would be significantly valuable for the efficient selection of therapeutic regimens and prediction of disease prognosis in patients with breast cancer.
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31
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Ma M, He W, Zhao K, Xue L, Xia S, Zhang B. Targeting aldehyde dehydrogenase for prostate cancer therapies. Front Oncol 2022; 12:1006340. [PMID: 36300093 PMCID: PMC9589344 DOI: 10.3389/fonc.2022.1006340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 09/26/2022] [Indexed: 11/25/2022] Open
Abstract
Prostate cancer (PCa) is the most common cancer in men in the United States. About 10 – 20% of PCa progress to castration-resistant PCa (CRPC), which is accompanied by metastasis and therapeutic resistance. Aldehyde dehydrogenase (ALDH) is famous as a marker of cancer stem-like cells in different cancer types, including PCa. Generally, ALDHs catalyze aldehyde oxidation into less toxic carboxylic acids and give cancers a survival advantage by reducing oxidative stress caused by aldehyde accumulation. In PCa, the expression of ALDHs is associated with a higher tumor stage and more lymph node metastasis. Functionally, increased ALDH activity makes PCa cells gain more capabilities in self-renewal and metastasis and reduces the sensitivity to castration and radiotherapy. Therefore, it is promising to target ALDH or ALDHhigh cells to eradicate PCa. However, challenges remain in moving the ALDH inhibitors to PCa therapy, potentially due to the toxicity of pan-ALDH inhibitors, the redundancy of ALDH isoforms, and the lack of explicit understanding of the metabolic signaling transduction details. For targeting PCa stem-like cells (PCSCs), different regulators have been revealed in ALDHhigh cells to control cell proliferation and tumorigenicity. ALDH rewires essential signaling transduction in PCa cells. It has been shown that ALDHs produce retinoic acid (RA), bind with androgen, and modulate diverse signaling. This review summarizes and discusses the pathways directly modulated by ALDHs, the crucial regulators that control the activities of ALDHhigh PCSCs, and the recent progress of ALDH targeted therapies in PCa. These efforts will provide insight into improving ALDH-targeted treatment.
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Affiliation(s)
| | | | | | | | - Siyuan Xia
- *Correspondence: Siyuan Xia, ; Baotong Zhang,
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Zhu C, Dong X, Wang X, Zheng Y, Qiu J, Peng Y, Xu J, Chai Z, Liu C. Multiple Roles of SIRT2 in Regulating Physiological and Pathological Signal Transduction. Genet Res (Camb) 2022; 2022:9282484. [PMID: 36101744 PMCID: PMC9444453 DOI: 10.1155/2022/9282484] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 07/01/2022] [Accepted: 07/08/2022] [Indexed: 11/18/2022] Open
Abstract
Sirtuin 2 (SIRT2), as a member of the sirtuin family, has representative features of evolutionarily highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase activity. In addition, SIRT2, as the only sirtuin protein colocalized with tubulin in the cytoplasm, has its own functions and characteristics. In recent years, studies have increasingly shown that SIRT2 can participate in the regulation of gene expression and regulate signal transduction in the metabolic pathway mainly through its post-translational modification of target genes; thus, SIRT2 has become a key centre in the metabolic pathway and participates in the pathological process of metabolic disorder-related diseases. In this paper, it is discussed that SIRT2 can regulate all aspects of gene expression, including epigenetic modification, replication, transcription and translation, and post-translational modification, which enables SIRT2 to participate in energy metabolism in life activities, and it is clarified that SIRT2 is involved in metabolic process-specific signal transduction mechanisms. Therefore, SIRT2 can be involved in metabolic disorder-related inflammation and oxidative stress, thereby triggering the occurrence of metabolic disorder-related diseases, such as neurodegenerative diseases, tumours, diabetes, and cardiovascular diseases. Currently, although the role of SIRT2 in some diseases is still controversial, given the multiple roles of SIRT2 in regulating physiological and pathological signal transduction, SIRT2 has become a key target for disease treatment. It is believed that with increasing research, the clinical application of SIRT2 will be promoted.
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Affiliation(s)
- Changhui Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Weifang Medical University, Weifang 261053, Shandong, China
- Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Xue Dong
- Department of Education, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Xiwei Wang
- Department of Anesthesiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Yingying Zheng
- Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Juanjuan Qiu
- Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250014, China
| | - Yanling Peng
- Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250014, China
| | - Jiajun Xu
- Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250014, China
| | - Zhengbin Chai
- Department of Clinical Laboratory Medicine, Shandong Public Health Clinical Center, Shandong University, Jinan 250102, China
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Chunyan Liu
- Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
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Schoenfeld DA, Zhou R, Zairis S, Su W, Steinbach N, Mathur D, Bansal A, Zachem AL, Tavarez B, Hasson D, Bernstein E, Rabadan R, Parsons R. Loss of PBRM1 Alters Promoter Histone Modifications and Activates ALDH1A1 to Drive Renal Cell Carcinoma. Mol Cancer Res 2022; 20:1193-1207. [PMID: 35412614 PMCID: PMC9357026 DOI: 10.1158/1541-7786.mcr-21-1039] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/22/2022] [Accepted: 04/06/2022] [Indexed: 02/07/2023]
Abstract
Subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in human malignancies. The PBAF complex is composed of multiple subunits, including the tumor-suppressor protein PBRM1 (BAF180), as well as ARID2 (BAF200), that are unique to this SWI/SNF complex. PBRM1 is mutated in various cancers, with a high mutation frequency in clear cell renal cell carcinoma (ccRCC). Here, we integrate RNA-seq, histone modification ChIP-seq, and ATAC-seq data to show that loss of PBRM1 results in de novo gains in H3K4me3 peaks throughout the epigenome, including activation of a retinoic acid biosynthesis and signaling gene signature. We show that one such target gene, ALDH1A1, which regulates a key step in retinoic acid biosynthesis, is consistently upregulated with PBRM1 loss in ccRCC cell lines and primary tumors, as well as non-malignant cells. We further find that ALDH1A1 increases the tumorigenic potential of ccRCC cells. Using biochemical methods, we show that ARID2 remains bound to other PBAF subunits after loss of PBRM1 and is essential for increased ALDH1A1 after loss of PBRM1, whereas other core SWI/SNF components are dispensable, including the ATPase subunit BRG1. In total, this study uses global epigenomic approaches to uncover novel mechanisms of PBRM1 tumor suppression in ccRCC. IMPLICATIONS This study implicates the SWI/SNF subunit and tumor-suppressor PBRM1 in the regulation of promoter histone modifications and retinoic acid biosynthesis and signaling pathways in ccRCC and functionally validates one such target gene, the aldehyde dehydrogenase ALDH1A1.
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Affiliation(s)
| | - Royce Zhou
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Sakellarios Zairis
- Department of Systems Biology, Columbia University, New York, NY, 10032, USA
| | - William Su
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Nicole Steinbach
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Deepti Mathur
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ankita Bansal
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Alexis L. Zachem
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Bertilia Tavarez
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Dan Hasson
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Emily Bernstein
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Raul Rabadan
- Department of Systems Biology, Columbia University, New York, NY, 10032, USA
| | - Ramon Parsons
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
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Wawruszak A, Luszczki J, Czerwonka A, Okon E, Stepulak A. Assessment of Pharmacological Interactions between SIRT2 Inhibitor AGK2 and Paclitaxel in Different Molecular Subtypes of Breast Cancer Cells. Cells 2022; 11:1211. [PMID: 35406775 PMCID: PMC8998062 DOI: 10.3390/cells11071211] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 03/29/2022] [Accepted: 03/31/2022] [Indexed: 12/20/2022] Open
Abstract
Breast carcinoma (BC) is the most commonly diagnosed type of cancer in women in the world. Although the advances in the treatment of BC patients are significant, numerous side effects, severe toxicity towards normal cells as well as the multidrug resistance (MDR) phenomenon restrict the effectiveness of the therapies used. Therefore, new active compounds which decrease the MDR, extend disease-free survival, thereby ameliorating the effectiveness of the current treatment regimens, are greatly needed. Histone deacetylase inhibitors (HDIs), including sirtuin inhibitors (SIRTi), are the epigenetic antitumor agents which induce a cytotoxic effect in different types of cancer cells, including BC cells. Currently, combined forms of therapy with two or even more chemotherapeutics are promising antineoplastic tools to obtain a better response to therapy and limit adverse effects. Thus, on the one hand, much more effective chemotherapeutics, e.g., sirtuin inhibitors (SIRTi), are in demand; on the other hand, combinations of accepted cytostatics are trialed. Thus, the aim of our research was to examine the combination effects of a renowned cytotoxic drug paclitaxel (PAX) and SIRT2 inhibitor AGK2 on the proliferation and viability of the T47D, MCF7, MDA-MB-231, MDA-MB-468, BT-549 and HCC1937 BC cells. Moreover, cell cycle arrest and apoptosis induction were explored. The type of pharmacological interactions between AGK2 and PAX in different molecular subtypes of BC cells was assessed using the advanced isobolographic method. Our findings demonstrated that the tested active agents singly inhibited viability and proliferation of BC cells as well as induced cell cycle arrest and apoptosis in the cell-dependent context. Additionally, AGK2 increased the antitumor effect of PAX in most BC cell lines. We observed that, depending on the BC cell lines, the combinations of tested drugs showed synergistic, additive or antagonistic pharmacological interaction. In conclusion, our studies demonstrated that the consolidated therapy with the use of AGK2 and PAX can be considered as a potential therapeutic regimen in the personalized cure of BC patients in the future.
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Affiliation(s)
- Anna Wawruszak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (A.C.); (E.O.); (A.S.)
| | - Jarogniew Luszczki
- Department of Pathophysiology, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Arkadiusz Czerwonka
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (A.C.); (E.O.); (A.S.)
| | - Estera Okon
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (A.C.); (E.O.); (A.S.)
| | - Andrzej Stepulak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (A.C.); (E.O.); (A.S.)
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GIT1 protects against breast cancer growth through negative regulation of Notch. Nat Commun 2022; 13:1537. [PMID: 35318302 PMCID: PMC8940956 DOI: 10.1038/s41467-022-28631-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 01/18/2022] [Indexed: 12/20/2022] Open
Abstract
Hyperactive Notch signalling is frequently observed in breast cancer and correlates with poor prognosis. However, relatively few mutations in the core Notch signalling pathway have been identified in breast cancer, suggesting that as yet unknown mechanisms increase Notch activity. Here we show that increased expression levels of GIT1 correlate with high relapse-free survival in oestrogen receptor-negative (ER(-)) breast cancer patients and that GIT1 mediates negative regulation of Notch. GIT1 knockdown in ER(-) breast tumour cells increased signalling downstream of Notch and activity of aldehyde dehydrogenase, a predictor of poor clinical outcome. GIT1 interacts with the Notch intracellular domain (ICD) and influences signalling by inhibiting the cytoplasm-to-nucleus transport of the Notch ICD. In xenograft experiments, overexpression of GIT1 in ER(-) cells prevented or reduced Notch-driven tumour formation. These results identify GIT1 as a modulator of Notch signalling and a guardian against breast cancer growth. Notch signalling is reported to be hyperactivated in oestrogen receptor-negative (ER-) breast cancer. Here the authors show that G protein-coupled receptor kinase-interacting protein 1 (GIT1) negatively regulates Notch signalling and tumour growth in ER- breast cancer by blocking Notch ICD nuclear translocation.
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Zanoni M, Bravaccini S, Fabbri F, Arienti C. Emerging Roles of Aldehyde Dehydrogenase Isoforms in Anti-cancer Therapy Resistance. Front Med (Lausanne) 2022; 9:795762. [PMID: 35299840 PMCID: PMC8920988 DOI: 10.3389/fmed.2022.795762] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 02/10/2022] [Indexed: 12/19/2022] Open
Abstract
Aldehyde dehydrogenases (ALDHs) are a family of detoxifying enzymes often upregulated in cancer cells and associated with therapeutic resistance. In humans, the ALDH family comprises 19 isoenzymes active in the majority of mammalian tissues. Each ALDH isoform has a specific differential expression pattern and most of them have individual functional roles in cancer. ALDHs are overexpressed in subpopulations of cancer cells with stem-like features, where they are involved in several processes including cellular proliferation, differentiation, detoxification and survival, participating in lipids and amino acid metabolism and retinoic acid synthesis. In particular, ALDH enzymes protect cancer cells by metabolizing toxic aldehydes in less reactive and more soluble carboxylic acids. High metabolic activity as well as conventional anticancer therapies contribute to aldehyde accumulation, leading to DNA double strand breaks (DSB) through the generation of reactive oxygen species (ROS) and lipid peroxidation. ALDH overexpression is crucial not only for the survival of cancer stem cells but can also affect immune cells of the tumour microenvironment (TME). The reduction of ROS amount and the increase in retinoic acid signaling impairs immunogenic cell death (ICD) inducing the activation and stability of immunosuppressive regulatory T cells (Tregs). Dissecting the role of ALDH specific isoforms in the TME can open new scenarios in the cancer treatment. In this review, we summarize the current knowledge about the role of ALDH isoforms in solid tumors, in particular in association with therapy-resistance.
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Affiliation(s)
- Michele Zanoni
- Biosciences Laboratory,IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | | | | | - Chiara Arienti
- Biosciences Laboratory,IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
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Wang HL, Ma X, Guan XY, Song C, Li GB, Yu YM, Yang LL. Potential Synthetic Lethality for Breast Cancer: A Selective Sirtuin 2 Inhibitor Combined with a Multiple Kinase Inhibitor Sorafenib. Pharmacol Res 2021; 177:106050. [PMID: 34973468 DOI: 10.1016/j.phrs.2021.106050] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 12/12/2021] [Accepted: 12/27/2021] [Indexed: 02/08/2023]
Abstract
Sorafenib is a clinically useful multiple kinase inhibitor for the treatment of kidney cancer, liver cancer and acute myelocytic leukemia, while it has shown weak efficacy in suppressing breast cancer. Since sirtuin2 (SIRT2) is an important epigenetic regulator and associated with several cancer types including breast cancer, development and evaluation of new SIRT2 inhibitors to probe their therapeutic potentials is currently desirable. A highly selective SIRT2 inhibitor named I was previously developed by us, which showed activity to inhibit non-small cell lung cancer cell lines in vitro. We herein report expanded screening of I and its structurally similar inactive compound II against other cancer cell lines, and found that I had a wide spectrum of anticancer activity while II had no such effects. The I-sorafenib combination treatment exerted obvious synergistic reduction on cell viability of MCF-7 cells. We observed that the combination treatment could suppress cell proliferation, survival and migration, arrest cell cycle at G0/G1 phase, and induce apoptosis in MCF-7 cells, when compared with the single treatment. In vivo studies revealed that the combination treatment showed stronger tumor growth inhibition (87%), comparing with I-(42.8%) or sorafenib-solely-treated groups (61.1%) in MCF-7 xenograft model. In conclusion, this work clearly revealed a potential synthetic lethality effect for I combined with sorafenib, and will probably offer a new strategy at least for breast cancer treatment.
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Affiliation(s)
- Hua-Li Wang
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, P. R. China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, P. R. China
| | - Xue Ma
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, P. R. China
| | - Xin-Yuan Guan
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, P. R. China
| | - Chen Song
- College of Food and Bioengineering, Xihua University, Sichuan 610039, P.R. China
| | - Guo-Bo Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Sichuan 610041, P. R. China
| | - Ya-Mei Yu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, P. R. China.
| | - Ling-Ling Yang
- College of Food and Bioengineering, Xihua University, Sichuan 610039, P.R. China.
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Parvanova I, Borziak K, Guarino J, Finkelstein J. A Platform for Integrating and Sharing Cancer Stem Cell Data. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2021; 2021:2320-2325. [PMID: 34891750 DOI: 10.1109/embc46164.2021.9630083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Advancements in cancer research and treatment have highlighted the need for standardization and sharing of cancer stem cell (CSC) data to facilitate research transparency and to promote collaboration within the scientific community. Although previous applications have attempted to gather and disseminate these data, currently no platform organizes the heterogeneous CSC information into a harmonized project-based framework. The aim of our platform, ReMeDy, is to provide an intelligent informatics solution integrating diverse CSC characteristics, outcomes information, and omics data across clinical, preclinical and in vitro studies. These heterogeneous data streams are organized within a multi-modular framework, subjected to a stringent validation by using standardized ontologies, and stored in a searchable format. To test usefulness of our approach for capturing diverse data related to CSCs, we integrated data from 52 publicly-available CSC projects. We validated the robustness of the platform, by efficiently organizing diverse data elements, and demonstrated its potential for promoting future knowledge discovery driven by aggregation of published data. Next steps include expanding number of uploaded CSC projects and developing additional data visualization tools. The platform is accessible through https://remedy.mssm.edu/.
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Liu C, Qiang J, Deng Q, Xia J, Deng L, Zhou L, Wang D, He X, Liu Y, Zhao B, Lv J, Yu Z, Lei QY, Shao ZM, Zhang XY, Zhang L, Liu S. ALDH1A1 activity in tumor-initiating cells remodels myeloid-derived suppressor cells to promote breast cancer progression. Cancer Res 2021; 81:5919-5934. [PMID: 34580061 DOI: 10.1158/0008-5472.can-21-1337] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 08/17/2021] [Accepted: 09/24/2021] [Indexed: 11/16/2022]
Abstract
Tumor-initiating cells (TIC) are associated with tumor initiation, growth, metastasis, and recurrence. Aldehyde dehydrogenase 1A1 (ALDH1A1) is a TIC marker in many cancers, including breast cancer. However the molecular mechanisms underlying ALDH1A1 functions in solid tumors remain largely unknown. Here we demonstrate that ALDH1A1 enzymatic activity facilitates breast tumor growth. Mechanistically, ALDH1A1 decreased the intracellular pH in breast cancer cells to promote phosphorylation of TAK1, activate NFκB signaling, and increase the secretion of granulocyte macrophage colony-stimulating factor (GM-CSF), which led to myeloid-derived suppressor cell (MDSC) expansion and immunosuppression. Furthermore, the ALDH1A1 inhibitor disulfiram and chemotherapeutic agent gemcitabine cooperatively inhibited breast tumor growth and tumorigenesis by purging ALDH+ TICs and activating T cell immunity. These findings elucidate how active ALDH1A1 modulates the immune system to promote tumor development, highlghting new therapeutic strategies for malignant breast cancer.
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Affiliation(s)
- Cuicui Liu
- Cancer Institute, Fudan University Shanghai Cancer Center
| | | | - Qiaodan Deng
- Cancer Institute, Fudan University Shanghai Cancer Center
| | - Jie Xia
- Cancer Institute, Fudan University Shanghai Cancer Center
| | - Lu Deng
- Stowers Institute for Medical Research
| | - Lei Zhou
- Cancer Institute, Fudan University Shanghai Cancer Center
| | | | - Xueyan He
- Life Science, University of Science and Technology of China
| | | | | | - Jinhui Lv
- Shanghai East Hospital, Tongji University School of Medicine
| | - Zuoren Yu
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Life Sciences and Technology
| | - Qun-Ying Lei
- Department of Oncology, Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University
| | - Zhi-Ming Shao
- Breast Surgery, Fudan University Shanghai Cancer Center
| | - Xiao-Yong Zhang
- The Institute of Science and Technology for Brain-inspired Intelligence, Fudan University
| | | | - Suling Liu
- Cancer Institute, Fudan University Shanghai Cancer Center
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Chen W, Wei W, Yu L, Ye Z, Huang F, Zhang L, Hu S, Cai C. Mammary Development and Breast Cancer: a Notch Perspective. J Mammary Gland Biol Neoplasia 2021; 26:309-320. [PMID: 34374886 PMCID: PMC8566423 DOI: 10.1007/s10911-021-09496-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 07/21/2021] [Indexed: 12/16/2022] Open
Abstract
Mammary gland development primarily occurs postnatally, and this unique process is complex and regulated by systemic hormones and local growth factors. The mammary gland is also a highly dynamic organ that undergoes profound changes at puberty and during the reproductive cycle. These changes are driven by mammary stem cells (MaSCs). Breast cancer is one of the most common causes of cancer-related death in women. Cancer stem cells (CSCs) play prominent roles in tumor initiation, drug resistance, tumor recurrence, and metastasis. The highly conserved Notch signaling pathway functions as a key regulator of the niche mediating mammary organogenesis and breast neoplasia. In this review, we discuss mechanisms by which Notch contributes to breast carcinoma pathology and suggest potentials for therapeutic targeting of Notch in breast cancer. In summary, we provide a comprehensive overview of Notch functions in regulating MaSCs, mammary development, and breast cancer.
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Affiliation(s)
- Weizhen Chen
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Wei Wei
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Liya Yu
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Zi Ye
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Fujing Huang
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Liyan Zhang
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Shiqi Hu
- DU-ANU Joint Science College, Shandong University, Weihai, 264200, China
| | - Cheguo Cai
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
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Zheng M, Hu C, Wu M, Chin YE. Emerging role of SIRT2 in non-small cell lung cancer. Oncol Lett 2021; 22:731. [PMID: 34429771 PMCID: PMC8371967 DOI: 10.3892/ol.2021.12992] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 04/16/2021] [Indexed: 11/14/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the most devastating cancer types, accounting for >80% of lung cancer cases. The median relative survival time of patients with NSCLC is <1 year. Lysine acetylation is a major post-translational modification that is required for various biological processes, and abnormal protein acetylation is associated with various diseases, including NSCLC. Protein deacetylases are currently considered cancer permissive partly due to malignant cells being sensitive to deacetylase inhibition. Sirtuin 2 (SIRT2), a primarily cytosolic nicotinamide adenine dinucleotide-dependent class III protein deacetylase, has been shown to catalyze the removal of acetyl groups from a wide range of proteins, including tubulin, ribonucleotide reductase regulatory subunit M2 and glucose-6-phosphate dehydrogenase. In addition, SIRT2 is also known to possess lysine fatty deacylation activity. Physiologically, SIRT2 serves as a regulator of the cell cycle and of cellular metabolism. It has been shown to play important roles in proliferation, migration and invasion during carcinogenesis. It is notable that both oncogenic and tumor suppressive functions of SIRT2 have been described in NSCLC and other cancer types, suggesting a context-specific role of SIRT2 in cancer progression. In addition, inhibition of SIRT2 exhibits a broad anticancer effect, indicating its potential as a therapeutic for NSCLC tumors with high expression of SIRT2. However, due to the diverse molecular and genetic characteristics of NSCLC, the context-specific function of SIRT2 remains to be determined. The current review investigated the functions of SIRT2 during NSCLC progression with regard to its regulation of metabolism, stem cell-like features and autophagy.
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Affiliation(s)
- Mengge Zheng
- Institute of Biology and Medical Sciences, Soochow University Medical College, Suzhou, Jiangsu 215123, P.R. China
| | - Changyong Hu
- Institute of Biology and Medical Sciences, Soochow University Medical College, Suzhou, Jiangsu 215123, P.R. China
| | - Meng Wu
- Institute of Biology and Medical Sciences, Soochow University Medical College, Suzhou, Jiangsu 215123, P.R. China
| | - Yue Eugene Chin
- Institute of Biology and Medical Sciences, Soochow University Medical College, Suzhou, Jiangsu 215123, P.R. China
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42
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Poturnajova M, Kozovska Z, Matuskova M. Aldehyde dehydrogenase 1A1 and 1A3 isoforms - mechanism of activation and regulation in cancer. Cell Signal 2021; 87:110120. [PMID: 34428540 PMCID: PMC8505796 DOI: 10.1016/j.cellsig.2021.110120] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/16/2021] [Accepted: 08/17/2021] [Indexed: 12/15/2022]
Abstract
In some types of human cancer, aldehyde dehydrogenases represent stemness markers and their expression is associated with advanced disease stages and poor prognosis. Although several biological functions are mediated by their product Retinoid acid, the molecular mechanism is tissue-dependent and only partially understood. In this review, we summarize the current knowledge about the role of ALDH in solid tumours, especially ALDH1A1 and ALDH1A3 isoforms, regarding the molecular mechanism of their transcription and regulation, and their crosstalk with main molecular pathways resulting in the excessive proliferation, chemoresistance, stem cells properties and invasiveness. The recent knowledge of the regulatory effect of lnRNA on ALDH1A1 and ALDH1A3 is discussed too.
Aldehyde dehydrogenases are important stem cell markers in many human cancer types. ALDH1A1 or ALDH1A3 activation participates in tumour progression, chemoresistance, stem-cell properties and invasiveness. ALDH1A1 interacts with oncogenic pathways Notch, NRF, CXCR4, Polycomb, MDR, and HOX.
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Affiliation(s)
- M Poturnajova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia.
| | - Z Kozovska
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia
| | - M Matuskova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia
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43
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Komaniecki G, Lin H. Lysine Fatty Acylation: Regulatory Enzymes, Research Tools, and Biological Function. Front Cell Dev Biol 2021; 9:717503. [PMID: 34368168 PMCID: PMC8339906 DOI: 10.3389/fcell.2021.717503] [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: 05/31/2021] [Accepted: 06/30/2021] [Indexed: 11/19/2022] Open
Abstract
Post-translational acylation of lysine side chains is a common mechanism of protein regulation. Modification by long-chain fatty acyl groups is an understudied form of lysine acylation that has gained increasing attention recently due to the characterization of enzymes that catalyze the addition and removal this modification. In this review we summarize what has been learned about lysine fatty acylation in the approximately 30 years since its initial discovery. We report on what is known about the enzymes that regulate lysine fatty acylation and their physiological functions, including tumorigenesis and bacterial pathogenesis. We also cover the effect of lysine fatty acylation on reported substrates. Generally, lysine fatty acylation increases the affinity of proteins for specific cellular membranes, but the physiological outcome depends greatly on the molecular context. Finally, we will go over the experimental tools that have been used to study lysine fatty acylation. While much has been learned about lysine fatty acylation since its initial discovery, the full scope of its biological function has yet to be realized.
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Affiliation(s)
- Garrison Komaniecki
- Graduate Field of Biochemistry, Molecular, and Cell Biology, Cornell University, Ithaca, NY, United States.,Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, United States
| | - Hening Lin
- Graduate Field of Biochemistry, Molecular, and Cell Biology, Cornell University, Ithaca, NY, United States.,Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, United States.,Howard Hughes Medical Institute, Cornell University, Ithaca, NY, United States
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44
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Chung KPS, Leung RWH, Lee TKW. Hampering Stromal Cells in the Tumor Microenvironment as a Therapeutic Strategy to Destem Cancer Stem Cells. Cancers (Basel) 2021; 13:3191. [PMID: 34202411 PMCID: PMC8268361 DOI: 10.3390/cancers13133191] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/30/2021] [Accepted: 06/21/2021] [Indexed: 12/27/2022] Open
Abstract
Cancer stem cells (CSCs) within the tumor bulk play crucial roles in tumor initiation, recurrence and therapeutic resistance. In addition to intrinsic regulation, a growing body of evidence suggests that the phenotypes of CSCs are also regulated extrinsically by stromal cells in the tumor microenvironment (TME). Here, we discuss the current knowledge of the interplay between stromal cells and cancer cells with a special focus on how stromal cells drive the stemness of cancer cells and immune evasive mechanisms of CSCs. Knowledge gained from the interaction between CSCs and stromal cells will provide a mechanistic basis for the development of novel therapeutic strategies for the treatment of cancers.
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Affiliation(s)
- Katherine Po Sin Chung
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China; (K.P.S.C.); (R.W.H.L.)
| | - Rainbow Wing Hei Leung
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China; (K.P.S.C.); (R.W.H.L.)
| | - Terence Kin Wah Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China; (K.P.S.C.); (R.W.H.L.)
- State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong, China
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45
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Yuan M, Zhao L, Li Y, Gao X, Zhang B, Zhang D, Li Y. Capsaicin on stem cell proliferation and fate determination - a novel perspective. Pharmacol Res 2021; 167:105566. [PMID: 33753245 DOI: 10.1016/j.phrs.2021.105566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 02/22/2021] [Accepted: 03/15/2021] [Indexed: 02/07/2023]
Abstract
Capsaicin (CAP), a member of the vanilloid family, is the main active component of chili peppers, which has been widely explored for its various pharmacological effects and influence on cell physiology, such as axonal growth and apoptosis of tumor cells. In particular, CAP plays a crucial role in determining the proliferation and fate specification of stem cells by modulating a variety of signaling pathways, such as PPARγ, C/EBPα and Notch signaling. Since CAP-mediated processes are complex and multifactorial, we hope to achieve a better understanding of these processes and their implications in clinical applications. This review aims to shed light on the influences and mechanisms of CAP on the actions of various stem cells in adults and discusses the role of CAP in the different process of stem cell behaviors, including proliferation and differentiation. Our purpose is to provide certain prospects for the application of CAP and stem cell therapy in treating diseases.
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Affiliation(s)
- Mengmeng Yuan
- State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China, 301617
| | - Lucy Zhao
- Institute for Pharmacy and Molecular Biotechnology, Functional Genomics, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany
| | - Yuhong Li
- State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China, 301617
| | - Xiumei Gao
- State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China, 301617
| | - Boli Zhang
- State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China, 301617
| | - Deqin Zhang
- State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China, 301617.
| | - Yue Li
- State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China, 301617.
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46
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Gaudelet T, Malod-Dognin N, Pržulj N. Integrative Data Analytic Framework to Enhance Cancer Precision Medicine. NETWORK AND SYSTEMS MEDICINE 2021; 4:60-73. [PMID: 33796878 PMCID: PMC8006589 DOI: 10.1089/nsm.2020.0015] [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] [Accepted: 02/15/2021] [Indexed: 12/20/2022] Open
Abstract
With the advancement of high-throughput biotechnologies, we increasingly accumulate biomedical data about diseases, especially cancer. There is a need for computational models and methods to sift through, integrate, and extract new knowledge from the diverse available data, to improve the mechanistic understanding of diseases and patient care. To uncover molecular mechanisms and drug indications for specific cancer types, we develop an integrative framework able to harness a wide range of diverse molecular and pan-cancer data. We show that our approach outperforms the competing methods and can identify new associations. Furthermore, it captures the underlying biology predictive of drug response. Through the joint integration of data sources, our framework can also uncover links between cancer types and molecular entities for which no prior knowledge is available. Our new framework is flexible and can be easily reformulated to study any biomedical problem.
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Affiliation(s)
- Thomas Gaudelet
- Department of Computer Science, University College London, London, United Kingdom
| | - Noël Malod-Dognin
- Department of Computer Science, University College London, London, United Kingdom
- Barcelona Supercomputing Center (BSC), Barcelona, Spain
| | - Nataša Pržulj
- Department of Computer Science, University College London, London, United Kingdom
- Barcelona Supercomputing Center (BSC), Barcelona, Spain
- ICREA, Barcelona, Spain
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47
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Yue D, Liu S, Zhang T, Wang Y, Qin G, Chen X, Zhang H, Wang D, Huang L, Wang F, Wang L, Zhao S, Zhang Y. NEDD9 promotes cancer stemness by recruiting myeloid-derived suppressor cells via CXCL8 in esophageal squamous cell carcinoma. Cancer Biol Med 2021; 18:705-720. [PMID: 33710809 PMCID: PMC8330544 DOI: 10.20892/j.issn.2095-3941.2020.0290] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 09/07/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Esophageal squamous cell carcinoma (ESCC) has high morbidity and mortality rates worldwide. Cancer stem cells (CSCs) may cause tumor initiation, metastasis, and recurrence and are also responsible for chemotherapy and radiotherapy failures. Myeloid-derived suppressor cells (MDSCs), in contrast, are known to be involved in mediating immunosuppression. Here, we aimed to investigate the mechanisms of interaction of CSCs and MDSCs in the tumor microenvironment. METHODS ESCC tissues and cell lines were evaluated. Neural precursor cell expressed, developmentally downregulated 9 (NEDD9) was knocked down and overexpressed by lentiviral transfection. Quantitative PCR, Western blot, immunohistochemistry, cell invasion, flow cytometry, cell sorting, multiplex chemokine profiling, and tumor growth analyses were performed. RESULTS Microarray analysis revealed 10 upregulated genes in esophageal CSCs. Only NEDD9 was upregulated in CSCs using the sphere-forming method. NEDD9 expression was correlated with tumor invasion (P = 0.0218), differentiation (P = 0.0153), and poor prognosis (P = 0.0373). Additionally, NEDD9 was required to maintain the stem-like phenotype. Screening of chemokine expression in ESCC cells with NEDD9 overexpression and knockdown showed that NEDD9 regulated C-X-C motif chemokine ligand 8 (CXCL8) expression via the ERK pathway. CXCL8 mediated the recruitment of MDSCs induced by NEDD9 in vitro and in vivo. MDSCs promoted the stemness of ESCC cells through NEDD9 via the Notch pathway. CONCLUSIONS As a marker of ESCC, NEDD9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathway to recruit MDSCs into the tumor, suggesting NEDD9 as a therapeutic target and novel prognostic marker for ESCC.
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Affiliation(s)
- Dongli Yue
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Shasha Liu
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Tengfei Zhang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yong Wang
- Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing 100730, China
- Biomed Innovation Center, Yehoo Group, Shenzhen 518067, China
| | - Guohui Qin
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Xinfeng Chen
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Huanyu Zhang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Dong Wang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Lan Huang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Feng Wang
- Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Liping Wang
- Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Song Zhao
- Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yi Zhang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- School of Life Sciences, Zhengzhou University, Zhengzhou 450052, China
- Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou 450052, China
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48
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Zheng Q, Zhang M, Zhou F, Zhang L, Meng X. The Breast Cancer Stem Cells Traits and Drug Resistance. Front Pharmacol 2021; 11:599965. [PMID: 33584277 PMCID: PMC7876385 DOI: 10.3389/fphar.2020.599965] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/17/2020] [Indexed: 12/13/2022] Open
Abstract
Drug resistance is a major challenge in breast cancer (BC) treatment at present. Accumulating studies indicate that breast cancer stem cells (BCSCs) are responsible for the BC drugs resistance, causing relapse and metastasis in BC patients. Thus, BCSCs elimination could reverse drug resistance and improve drug efficacy to benefit BC patients. Consequently, mastering the knowledge on the proliferation, resistance mechanisms, and separation of BCSCs in BC therapy is extremely helpful for BCSCs-targeted therapeutic strategies. Herein, we summarize the principal BCSCs surface markers and signaling pathways, and list the BCSCs-related drug resistance mechanisms in chemotherapy (CT), endocrine therapy (ET), and targeted therapy (TT), and display therapeutic strategies for targeting BCSCs to reverse drug resistance in BC. Even more importantly, more attention should be paid to studies on BCSC-targeted strategies to overcome the drug resistant dilemma of clinical therapies in the future.
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Affiliation(s)
- Qinghui Zheng
- Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Mengdi Zhang
- MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Fangfang Zhou
- Institutes of Biology and Medical Science, Soochow University, Suzhou, China
| | - Long Zhang
- MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Xuli Meng
- Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China
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49
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Shan NL, Shin Y, Yang G, Furmanski P, Suh N. Breast cancer stem cells: A review of their characteristics and the agents that affect them. Mol Carcinog 2021; 60:73-100. [PMID: 33428807 DOI: 10.1002/mc.23277] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/21/2020] [Accepted: 12/22/2020] [Indexed: 12/17/2022]
Abstract
The evolving concept that cancer stem cells (CSCs) are the driving element in cancer development, evolution and heterogeneity, has overridden the previous model of a tumor consisting of cells all with similar sequentially acquired mutations and a similar potential for renewal, invasion and metastasis. This paradigm shift has focused attention on therapeutically targeting CSCs directly as a means of eradicating the disease. In breast cancers, CSCs can be identified by cell surface markers and are characterized by their ability to self-renew and differentiate, resist chemotherapy and radiation, and initiate new tumors upon serial transplantation in xenografted mice. These functional properties of CSCs are regulated by both intracellular and extracellular factors including pluripotency-related transcription factors, intracellular signaling pathways and external stimuli. Several classes of natural products and synthesized compounds have been studied to target these regulatory elements and force CSCs to lose stemness and/or terminally differentiate and thereby achieve a therapeutic effect. However, realization of an effective treatment for breast cancers, focused on the biological effects of these agents on breast CSCs, their functions and signaling, has not yet been achieved. In this review, we delineate the intrinsic and extrinsic factors identified to date that control or promote stemness in breast CSCs and provide a comprehensive compilation of potential agents that have been studied to target breast CSCs, transcription factors and stemness-related signaling. Our aim is to stimulate further study of these agents that could become the basis for their use as stand-alone treatments or components of combination therapies effective against breast cancers.
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Affiliation(s)
- Naing L Shan
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA
| | - Yoosub Shin
- Yonsei University, College of Medicine, Seoul, Republic of Korea
| | - Ge Yang
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA
| | - Philip Furmanski
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.,Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
| | - Nanjoo Suh
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.,Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
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50
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Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis. Cells 2021; 10:cells10010094. [PMID: 33430387 PMCID: PMC7827494 DOI: 10.3390/cells10010094] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/23/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023] Open
Abstract
The Notch signaling pathway is a critical player in embryogenesis but also plays various roles in tumorigenesis, with both tumor suppressor and oncogenic activities. Mutations, deletions, amplifications, or over-expression of Notch receptors, ligands, and a growing list of downstream Notch-activated genes have by now been described for most human cancer types. Yet, it often remains unclear what may be the functional impact of these changes for tumor biology, initiation, and progression, for cancer therapy, and for personalized medicine. Emerging data indicate that Notch signaling can also contribute to increased aggressive properties such as invasion, tumor heterogeneity, angiogenesis, or tumor cell dormancy within solid cancer tissues; especially in epithelial cancers, which are in the center of this review. Notch further supports the “stemness” of cancer cells and helps define the stem cell niche for their long-term survival, by integrating the interaction between cancer cells and the cells of the tumor microenvironment (TME). The complexity of Notch crosstalk with other signaling pathways and its roles in cell fate and trans-differentiation processes such as epithelial-to-mesenchymal transition (EMT) point to this pathway as a decisive player that may tip the balance between tumor suppression and promotion, differentiation and invasion. Here we not only review the literature, but also explore genomic databases with a specific focus on Notch signatures, and how they relate to different stages in tumor development. Altered Notch signaling hereby plays a key role for tumor cell survival and coping with a broad spectrum of vital issues, contributing to failed therapies, poor patient outcome, and loss of lives.
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