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Thakur R, Mullen NJ, Mehla K, Singh PK. Tumor-stromal metabolic crosstalk in pancreatic cancer. Trends Cell Biol 2025:S0962-8924(25)00109-6. [PMID: 40425415 DOI: 10.1016/j.tcb.2025.04.007] [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: 10/24/2024] [Revised: 04/23/2025] [Accepted: 04/25/2025] [Indexed: 05/29/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a dire prognosis. Standard-of-care chemotherapy regimens offer marginal survival benefit and carry risk of severe toxicity, while immunotherapy approaches have uniformly failed in clinical trials. Extensive desmoplasia in the PDAC tumor microenvironment (TME) disrupts blood flow to and from the tumor, thereby creating a nutrient-depleted, hypoxic, and acidic milieu that suppresses the function of antitumor immune cells and imparts chemotherapy resistance. Additionally, recent seminal studies have demonstrated crucial roles for metabolic crosstalk - the exchange of metabolites between PDAC cells and stromal cell populations in the TME - in establishing and maintaining core malignant behaviors of PDAC: tumor growth, metastasis, immune evasion, and therapy resistance. In this review, we provide a conceptual overview of metabolic crosstalk and how it evolves under various selection pressures in the TME, analyze the landscape of proposed tumorigenic metabolic crosstalk pathways, and highlight potentially druggable nodes.
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Affiliation(s)
- Ravi Thakur
- Department of Oncology Science, University of Oklahoma College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Nicholas J Mullen
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kamiya Mehla
- Department of Oncology Science, University of Oklahoma College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Pankaj K Singh
- Department of Oncology Science, University of Oklahoma College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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2
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Moura JP, Oliveira PJ, Urbano AM. Mitochondrial classic metabolism and its often-underappreciated facets. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167839. [PMID: 40220877 DOI: 10.1016/j.bbadis.2025.167839] [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: 03/07/2025] [Accepted: 04/07/2025] [Indexed: 04/14/2025]
Abstract
For many decades, mitochondria were essentially regarded as the main providers of the adenosine triphosphate (ATP) required to maintain the viability and function of eukaryotic cells, thus the widely popular metaphor "powerhouses of the cell". Besides ATP generation - via intermediary metabolism - these intracellular organelles have also traditionally been known, albeit to a lesser degree, for their notable role in biosynthesis, both as generators of biosynthetic intermediates and/or as the sites of biosynthesis. From the 1990s onwards, the concept of mitochondria as passive organelles providing the rest of the cell, from which they were otherwise isolated, with ATP and biomolecules on an on-demand basis has been challenged by a series of paradigm-shifting discoveries. Namely, it was shown that mitochondria act as signaling effectors to upregulate ATP generation in response to growth-promoting stimuli and are actively engaged, through signaling and epigenetics, in the regulation of a plethora of cellular processes, ultimately deciding cell function and fate. With the focus of mitochondrial research increasingly placed in these "non-classical" functions, the centrality of mitochondrial intermediary metabolism to other mitochondrial functions tends to be overlooked. In this article, we revisit mitochondrial intermediary metabolism and illustrate how its intermediates, by-products and molecular machinery underpin other mitochondrial functions. A certain emphasis is given to frequently overlooked mitochondrial functions, namely the biosynthesis of iron-sulfur (Fe-S) clusters, the only known function shared by all mitochondria and mitochondrion-related organelles. The generation of reactive oxygen species (ROS) and their putative role in signaling is also discussed in detail.
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Affiliation(s)
- João P Moura
- Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
| | - Paulo J Oliveira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal.
| | - Ana M Urbano
- Molecular Physical-Chemistry R&D Unit, Centre for Investigation in Environment, Genetics and Oncobiology (CIMAGO), Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
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3
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Yu F, Chen J, Wang X, Hou S, Li H, Yao Y, He Y, Chen K. Metabolic reprogramming of peritoneal mesothelial cells in peritoneal dialysis-associated fibrosis: therapeutic targets and strategies. Cell Commun Signal 2025; 23:114. [PMID: 40016825 PMCID: PMC11866825 DOI: 10.1186/s12964-025-02113-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/17/2025] [Indexed: 03/01/2025] Open
Abstract
Peritoneal dialysis (PD) is considered a life-saving treatment for end-stage renal disease. However, prolonged PD use can lead to the development of peritoneal fibrosis (PF), diminishing its efficacy. Peritoneal mesothelial cells (PMCs) are key initiators of PF when they become damaged. Exposure to high glucose‑based peritoneal dialysis fluids (PDFs) contributes to PF development by directly affecting highly metabolically active PMCs. Recent research indicates that PMCs undergo metabolic reprogramming when exposed to high-glucose PDFs, including enhanced glycolysis, impaired oxidative phosphorylation, abnormal lipid metabolism, and mitochondrial dysfunction. Although this metabolic transition temporarily compensates for the cellular damage and maintains energy levels, its long-term impact on peritoneal tissue is concerning. Multiple studies have identified a close association between this shift in energy metabolism and PF, and may promote the progression of PF through various molecular mechanisms. This review explores recent findings regarding the role and mechanism of PMC metabolic reprogramming in PF progression. Moreover, it provides a summary of potential therapeutic strategies aimed at various metabolic processes, including glucose metabolism, lipid metabolism, and mitochondrial function. The review establishes that targeting metabolic reprogramming in PMCs may be a novel strategy for preventing and treating PD-associated fibrosis.
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Affiliation(s)
- Fang Yu
- Department of Nephrology, Daping Hospital, Army Medical Center, Army Medical University, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China
- Chongqing Key Laboratory of Precision Diagnosis and Treatment for Kidney Diseases, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China
| | - Jia Chen
- Department of Nephrology, Daping Hospital, Army Medical Center, Army Medical University, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China
- Chongqing Key Laboratory of Precision Diagnosis and Treatment for Kidney Diseases, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China
| | - Xiaoyue Wang
- Department of Nephrology, Daping Hospital, Army Medical Center, Army Medical University, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China
- Chongqing Key Laboratory of Precision Diagnosis and Treatment for Kidney Diseases, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China
| | - Shihui Hou
- Department of Nephrology, Daping Hospital, Army Medical Center, Army Medical University, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China
| | - Hong Li
- Department of Nephrology, Daping Hospital, Army Medical Center, Army Medical University, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China
| | - Yaru Yao
- Department of Nephrology, Daping Hospital, Army Medical Center, Army Medical University, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China
| | - Yani He
- Department of Nephrology, Daping Hospital, Army Medical Center, Army Medical University, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China.
- Chongqing Key Laboratory of Precision Diagnosis and Treatment for Kidney Diseases, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China.
- State Key Laboratory of Trauma and Chemical poisoning, Burns and Combined Injury, Army Medical University, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China.
| | - Kehong Chen
- Department of Nephrology, Daping Hospital, Army Medical Center, Army Medical University, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China.
- Chongqing Key Laboratory of Precision Diagnosis and Treatment for Kidney Diseases, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China.
- State Key Laboratory of Trauma and Chemical poisoning, Burns and Combined Injury, Army Medical University, NO. 10 Changjiang Road, Yuzhong District, Chongqing, 400042, China.
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Li J, Liu J, Wu Y, Sun Y, Huang G, Jin M. α-Hederin inhibited pancreatic cancer cell malignant progression by inhibiting LDHA-mediated glycolysis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-024-03621-7. [PMID: 39969605 DOI: 10.1007/s00210-024-03621-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 11/08/2024] [Indexed: 02/20/2025]
Abstract
α-Hederin is a pentacyclic triterpenoid saponin extracted from Pulsatilla chinensis, which is known to suppress cancer cell proliferation. However, the role of this compound in pancreatic cancer cells remains unclear. The aim of this study was to reveal the docking molecular and the regulatory mechanism of α-hederin in pancreatic cancer. Here, we cultured Capan-1 and BxPC-3 cells and treated with different doses of α-hederin. Cell proliferation, migration, and apoptosis were detected using CCK8, EdU, Transwell, wound healing assay, and flow cytometer apoptosis assay. The in vivo experiment using subcutaneous tumor and caudal vein metastasis model to evaluate the inhibit effect of α-hederin Capan-1 cell tumor growth and metastasis. Proteomics were used to reveal the regulatory mechanism. The result shows that α-hederin treatment inhibits cell proliferation and invasion in concentration dependence way in both vivo and in vitro. The result shows that the IC50 for both Capan-1 and BxPC-3 were 32.5 Mµ and 15 Mµ, respectively. Flow cytometer apoptosis assay shows that α-hederin treatment promotion cell apoptosis in both Capan-1 and BxPC-3 cells. Proteomics and immunofluorescence detection confirmed that α-hederin treatment downregulated lactate dehydrogenase A (LDHA) expression and inhibited glycolysis. Molecular docking of α-hederin and LDHA proteins further confirmed that LDHA is a target of α-hederin. Taken together, this study confirms that α-hederin inhibits pancreatic cancer cell proliferation and invasion by inhibiting LDHA-mediated glycolysis. LDHA may be a direct target of α-hederin in pancreatic cancer.
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Affiliation(s)
- Jingjing Li
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China
| | - Jiao Liu
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China
| | - Yue Wu
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Yi Sun
- Obstetrics and Gynecology Department, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, No.1111, XianXia Road, Shanghai, 200336, China.
| | - Gang Huang
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China.
| | - Mingming Jin
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China.
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Chen J, Huang Z, Chen Y, Tian H, Chai P, Shen Y, Yao Y, Xu S, Ge S, Jia R. Lactate and lactylation in cancer. Signal Transduct Target Ther 2025; 10:38. [PMID: 39934144 PMCID: PMC11814237 DOI: 10.1038/s41392-024-02082-x] [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: 06/28/2024] [Revised: 10/07/2024] [Accepted: 11/18/2024] [Indexed: 02/13/2025] Open
Abstract
Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings, particularly in intricate conditions such as cancer. Specifically, lactate has been demonstrated to be pivotal in molding the tumor microenvironment (TME) through its effects on different cell populations. Within tumor cells, lactate impacts cell signaling pathways, augments the lactate shuttle process, boosts resistance to oxidative stress, and contributes to lactylation. In various cellular populations, the interplay between lactate and immune cells governs processes such as cell differentiation, immune response, immune surveillance, and treatment effectiveness. Furthermore, communication between lactate and stromal/endothelial cells supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, and drug resistance. Focusing on lactate production and transport, specifically through lactate dehydrogenase (LDH) and monocarboxylate transporters (MCT), has shown promise in the treatment of cancer. Inhibitors targeting LDH and MCT act as both tumor suppressors and enhancers of immunotherapy, leading to a synergistic therapeutic effect when combined with immunotherapy. The review underscores the importance of lactate in tumor progression and provides valuable perspectives on potential therapeutic approaches that target the vulnerability of lactate metabolism, highlighting the Heel of Achilles for cancer treatment.
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Affiliation(s)
- Jie Chen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Ziyue Huang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Ya Chen
- Department of Radiology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
| | - Hao Tian
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Peiwei Chai
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Yongning Shen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
| | - Yiran Yao
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Shiqiong Xu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China.
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China.
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China.
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Aden D, Sureka N, Zaheer S, Chaurasia JK, Zaheer S. Metabolic Reprogramming in Cancer: Implications for Immunosuppressive Microenvironment. Immunology 2025; 174:30-72. [PMID: 39462179 DOI: 10.1111/imm.13871] [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: 05/18/2024] [Revised: 10/07/2024] [Accepted: 10/09/2024] [Indexed: 10/29/2024] Open
Abstract
Cancer is a complex and heterogeneous disease characterised by uncontrolled cell growth and proliferation. One hallmark of cancer cells is their ability to undergo metabolic reprogramming, which allows them to sustain their rapid growth and survival. This metabolic reprogramming creates an immunosuppressive microenvironment that facilitates tumour progression and evasion of the immune system. In this article, we review the mechanisms underlying metabolic reprogramming in cancer cells and discuss how these metabolic alterations contribute to the establishment of an immunosuppressive microenvironment. We also explore potential therapeutic strategies targeting metabolic vulnerabilities in cancer cells to enhance immune-mediated anti-tumour responses. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02044861, NCT03163667, NCT04265534, NCT02071927, NCT02903914, NCT03314935, NCT03361228, NCT03048500, NCT03311308, NCT03800602, NCT04414540, NCT02771626, NCT03994744, NCT03229278, NCT04899921.
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Affiliation(s)
- Durre Aden
- Department of Pathology, Hamdard Institute of Medical Science and Research, New Delhi, India
| | - Niti Sureka
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| | - Samreen Zaheer
- Department of Radiotherapy, Jawaharlal Nehru Medical College, AMU, Aligarh, India
| | | | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
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7
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Ciepła J, Smolarczyk R. Tumor hypoxia unveiled: insights into microenvironment, detection tools and emerging therapies. Clin Exp Med 2024; 24:235. [PMID: 39361163 PMCID: PMC11449960 DOI: 10.1007/s10238-024-01501-1] [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: 06/17/2024] [Accepted: 09/26/2024] [Indexed: 10/05/2024]
Abstract
Hypoxia is one of the defining characteristics of the tumor microenvironment (TME) in solid cancers. It has a major impact on the growth and spread of malignant cells as well as their resistance to common treatments like radiation and chemotherapy. Here, we explore the complex functions of hypoxia in the TME and investigate its effects on angiogenesis, immunological evasion, and cancer cell metabolism. For prognostic and therapeutic reasons, hypoxia identification is critical, and recent developments in imaging and molecular methods have enhanced our capacity to precisely locate underoxygenated areas inside tumors. Furthermore, targeted therapies that take advantage of hypoxia provide a potential new direction in the treatment of cancer. Therapeutic approaches that specifically target hypoxic conditions in tumors without causing adverse effects are being led by hypoxia-targeted nanocarriers and hypoxia-activated prodrugs (HAPs). This review provides an extensive overview of this dynamic and clinically significant area of oncology research by synthesizing current knowledge about the mechanisms of hypoxia in cancer, highlighting state-of-the-art detection methodologies, and assessing the potential and efficacy of hypoxia-targeted therapies.
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Affiliation(s)
- Joanna Ciepła
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej Street 15, 44-102, Gliwice, Poland
| | - Ryszard Smolarczyk
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej Street 15, 44-102, Gliwice, Poland.
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8
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Yang J, Shay C, Saba NF, Teng Y. Cancer metabolism and carcinogenesis. Exp Hematol Oncol 2024; 13:10. [PMID: 38287402 PMCID: PMC10826200 DOI: 10.1186/s40164-024-00482-x] [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: 10/23/2023] [Accepted: 01/22/2024] [Indexed: 01/31/2024] Open
Abstract
Metabolic reprogramming is an emerging hallmark of cancer cells, enabling them to meet increased nutrient and energy demands while withstanding the challenging microenvironment. Cancer cells can switch their metabolic pathways, allowing them to adapt to different microenvironments and therapeutic interventions. This refers to metabolic heterogeneity, in which different cell populations use different metabolic pathways to sustain their survival and proliferation and impact their response to conventional cancer therapies. Thus, targeting cancer metabolic heterogeneity represents an innovative therapeutic avenue with the potential to overcome treatment resistance and improve therapeutic outcomes. This review discusses the metabolic patterns of different cancer cell populations and developmental stages, summarizes the molecular mechanisms involved in the intricate interactions within cancer metabolism, and highlights the clinical potential of targeting metabolic vulnerabilities as a promising therapeutic regimen. We aim to unravel the complex of metabolic characteristics and develop personalized treatment approaches to address distinct metabolic traits, ultimately enhancing patient outcomes.
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Affiliation(s)
- Jianqiang Yang
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 201 Dowman Dr, Atlanta, GA, 30322, USA
| | - Chloe Shay
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30322, USA
| | - Nabil F Saba
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 201 Dowman Dr, Atlanta, GA, 30322, USA
| | - Yong Teng
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 201 Dowman Dr, Atlanta, GA, 30322, USA.
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30322, USA.
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Wang Y, Patti GJ. The Warburg effect: a signature of mitochondrial overload. Trends Cell Biol 2023; 33:1014-1020. [PMID: 37117116 PMCID: PMC10600323 DOI: 10.1016/j.tcb.2023.03.013] [Citation(s) in RCA: 75] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/28/2023] [Accepted: 03/29/2023] [Indexed: 04/30/2023]
Abstract
A long-standing question in cancer biology has been why oxygenated tumors ferment the majority of glucose they consume to lactate rather than oxidizing it in their mitochondria, a phenomenon known as the 'Warburg effect.' An abundance of evidence shows not only that most cancer cells have fully functional mitochondria but also that mitochondrial activity is important to proliferation. It is therefore difficult to rationalize the metabolic benefit of cancer cells switching from respiration to fermentation. An emerging perspective is that rather than mitochondrial metabolism being suppressed in tumors, as is often suggested, mitochondrial activity increases to the level of saturation. As such, the Warburg effect becomes a signature of excess glucose being released as lactate due to mitochondrial overload.
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Affiliation(s)
- Yahui Wang
- Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Gary J Patti
- Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO 63130, USA; Department of Medicine, Washington University in St. Louis, St. Louis, MO 63130, USA; Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63130, USA.
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10
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Su Z, Zhang G, Li X, Zhang H. Inverse correlation between Alzheimer's disease and cancer from the perspective of hypoxia. Neurobiol Aging 2023; 131:59-73. [PMID: 37572528 DOI: 10.1016/j.neurobiolaging.2023.07.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 06/02/2023] [Accepted: 07/03/2023] [Indexed: 08/14/2023]
Abstract
Sporadic Alzheimer's disease and cancer remain epidemiologically inversely related, and exploring the reverse pathogenesis is important for our understanding of both. Cognitive dysfunctions in Alzheimer's disease (AD) might result from the depletion of adaptive reserves in the brain. Energy storage in the brain is limited and is dynamically regulated by neurovascular and neurometabolic coupling. The research on neurodegenerative diseases has been dominated by the neurocentric view that neuronal defects cause the diseases. However, the proposal of the 2-hit vascular hypothesis in AD led us to focus on alterations in the vasculature, especially hypoperfusion. Chronic hypoxia is a feature shared by AD and cancer. It is interesting how contradicting chronic hypoxia's effects on both cancer and AD are. In this article, we discuss the potential links between the 2 diseases' etiology, from comparable upstream circumstances to diametrically opposed downstream effects. We suggest opposing potential mechanisms, including upregulation and downregulation of hypoxia-inducible factor-1α, the Warburg and reverse-Warburg effects, lactate-mediated intracellular acidic and alkaline conditions, and VDAC1-mediated apoptosis and antiapoptosis, and search for regulators that may be identified as the crossroads between cancer and AD.
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Affiliation(s)
- Zhan Su
- Department of Neurology and Neuroscience Centre, The First Hospital of Jilin University, Changchun, China
| | - Guimei Zhang
- Department of Neurology and Neuroscience Centre, The First Hospital of Jilin University, Changchun, China
| | - Xiangting Li
- Department of Neurology and Neuroscience Centre, The First Hospital of Jilin University, Changchun, China
| | - Haining Zhang
- Department of Neurology and Neuroscience Centre, The First Hospital of Jilin University, Changchun, China.
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11
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Liu QJ, Yuan W, Yang P, Shao C. Role of glycolysis in diabetic atherosclerosis. World J Diabetes 2023; 14:1478-1492. [PMID: 37970130 PMCID: PMC10642412 DOI: 10.4239/wjd.v14.i10.1478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/16/2023] [Accepted: 09/14/2023] [Indexed: 10/09/2023] Open
Abstract
Diabetes mellitus is a kind of typical metabolic disorder characterized by elevated blood sugar levels. Atherosclerosis (AS) is one of the most common complications of diabetes. Modern lifestyles and trends that promote overconsumption and unhealthy practices have contributed to an increase in the annual incidence of diabetic AS worldwide, which has created a heavy burden on society. Several studies have shown the significant effects of glycolysis-related changes on the occurrence and development of diabetic AS, which may serve as novel thera-peutic targets for diabetic AS in the future. Glycolysis is an important metabolic pathway that generates energy in various cells of the blood vessel wall. In particular, it plays a vital role in the physiological and pathological activities of the three important cells, Endothelial cells, macrophages and vascular smooth muscle cells. There are lots of similar mechanisms underlying diabetic and common AS, the former is more complex. In this article, we describe the role and mechanism underlying glycolysis in diabetic AS, as well as the therapeutic targets, such as trained immunity, microRNAs, gut microbiota, and associated drugs, with the aim to provide some new perspectives and potentially feasible programs for the treatment of diabetic AS in the foreseeable future.
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Affiliation(s)
- Qian-Jia Liu
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Wei Yuan
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Ping Yang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Chen Shao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
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12
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To KKW, Cho WC. Drug Repurposing to Circumvent Immune Checkpoint Inhibitor Resistance in Cancer Immunotherapy. Pharmaceutics 2023; 15:2166. [PMID: 37631380 PMCID: PMC10459070 DOI: 10.3390/pharmaceutics15082166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/07/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023] Open
Abstract
Immune checkpoint inhibitors (ICI) have achieved unprecedented clinical success in cancer treatment. However, drug resistance to ICI therapy is a major hurdle that prevents cancer patients from responding to the treatment or having durable disease control. Drug repurposing refers to the application of clinically approved drugs, with characterized pharmacological properties and known adverse effect profiles, to new indications. It has also emerged as a promising strategy to overcome drug resistance. In this review, we summarized the latest research about drug repurposing to overcome ICI resistance. Repurposed drugs work by either exerting immunostimulatory activities or abolishing the immunosuppressive tumor microenvironment (TME). Compared to the de novo drug design strategy, they provide novel and affordable treatment options to enhance cancer immunotherapy that can be readily evaluated in the clinic. Biomarkers are exploited to identify the right patient population to benefit from the repurposed drugs and drug combinations. Phenotypic screening of chemical libraries has been conducted to search for T-cell-modifying drugs. Genomics and integrated bioinformatics analysis, artificial intelligence, machine and deep learning approaches are employed to identify novel modulators of the immunosuppressive TME.
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Affiliation(s)
- Kenneth K. W. To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
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13
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How Warburg-Associated Lactic Acidosis Rewires Cancer Cell Energy Metabolism to Resist Glucose Deprivation. Cancers (Basel) 2023; 15:cancers15051417. [PMID: 36900208 PMCID: PMC10000466 DOI: 10.3390/cancers15051417] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/17/2023] [Accepted: 02/21/2023] [Indexed: 02/25/2023] Open
Abstract
Lactic acidosis, a hallmark of solid tumour microenvironment, originates from lactate hyperproduction and its co-secretion with protons by cancer cells displaying the Warburg effect. Long considered a side effect of cancer metabolism, lactic acidosis is now known to play a major role in tumour physiology, aggressiveness and treatment efficiency. Growing evidence shows that it promotes cancer cell resistance to glucose deprivation, a common feature of tumours. Here we review the current understanding of how extracellular lactate and acidosis, acting as a combination of enzymatic inhibitors, signal, and nutrient, switch cancer cell metabolism from the Warburg effect to an oxidative metabolic phenotype, which allows cancer cells to withstand glucose deprivation, and makes lactic acidosis a promising anticancer target. We also discuss how the evidence about lactic acidosis' effect could be integrated in the understanding of the whole-tumour metabolism and what perspectives it opens up for future research.
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14
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Targeting hypoxia-related metabolism molecules: How to improve tumour immune and clinical treatment? Biomed Pharmacother 2022; 156:113917. [DOI: 10.1016/j.biopha.2022.113917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 11/20/2022] Open
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15
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The Juggernaut of Adaptive Metabolism in Cancers: Implications and Therapeutic Targets. Cancers (Basel) 2022; 14:cancers14215202. [DOI: 10.3390/cancers14215202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 10/20/2022] [Indexed: 11/16/2022] Open
Abstract
The disease of cancer instills a sense of fear and dread among patients and the next of kin who are indirectly affected by the deteriorating quality of life of their loved ones [...]
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16
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Chen G, Wu K, Li H, Xia D, He T. Role of hypoxia in the tumor microenvironment and targeted therapy. Front Oncol 2022; 12:961637. [PMID: 36212414 PMCID: PMC9545774 DOI: 10.3389/fonc.2022.961637] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 09/01/2022] [Indexed: 11/21/2022] Open
Abstract
Tumor microenvironment (TME), which is characterized by hypoxia, widely exists in solid tumors. As a current research hotspot in the TME, hypoxia is expected to become a key element to break through the bottleneck of tumor treatment. More and more research results show that a variety of biological behaviors of tumor cells are affected by many factors in TME which are closely related to hypoxia. In order to inhibiting the immune response in TME, hypoxia plays an important role in tumor cell metabolism and anti-apoptosis. Therefore, exploring the molecular mechanism of hypoxia mediated malignant tumor behavior and therapeutic targets is expected to provide new ideas for anti-tumor therapy. In this review, we discussed the effects of hypoxia on tumor behavior and its interaction with TME from the perspectives of immune cells, cell metabolism, oxidative stress and hypoxia inducible factor (HIF), and listed the therapeutic targets or signal pathways found so far. Finally, we summarize the current therapies targeting hypoxia, such as glycolysis inhibitors, anti-angiogenesis drugs, HIF inhibitors, hypoxia-activated prodrugs, and hyperbaric medicine.
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Affiliation(s)
- Gaoqi Chen
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Kaiwen Wu
- Department of Gastroenterology, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
| | - Hao Li
- Deparment of Neurology, Affiliated Hospital of Jiangsu University, Jiang Su University, Zhenjiang, China
| | - Demeng Xia
- Luodian Clinical Drug Research Center, Shanghai Baoshan Luodian Hospital, Shanghai University, Shanghai, China
- *Correspondence: Demeng Xia, ; Tianlin He,
| | - Tianlin He
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- *Correspondence: Demeng Xia, ; Tianlin He,
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17
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Historical perspective of tumor glycolysis: A century with Otto Warburg. Semin Cancer Biol 2022; 86:325-333. [PMID: 35809880 DOI: 10.1016/j.semcancer.2022.07.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/27/2022] [Accepted: 07/05/2022] [Indexed: 12/12/2022]
Abstract
Tumors have long been known to rewire their metabolism to endorse their proliferation, growth, survival, and invasiveness. One of the common characteristics of these alterations is the enhanced glucose uptake and its subsequent transformation into lactic acid by means of glycolysis, regardless the availability of oxygen or the mitochondria effectiveness. This phenomenon is called the "Warburg effect", which has turned into a century of age now, since its first disclosure by German physiologist Otto Heinrich Warburg. Since then, this peculiar metabolic switch in tumors has been addressed by extensive studies covering several areas of research. In this historical perspective, we aim at illustrating the evolution of these studies over time and their implication in various fields of science.
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18
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Qu D, Zou X, Liu Z. Propofol modulates glycolysis reprogramming of ovarian tumor via restraining circular RNA-zinc finger RNA-binding protein/microRNA-212-5p/superoxide dismutase 2 axis. Bioengineered 2022; 13:11881-11892. [PMID: 35543376 PMCID: PMC9275929 DOI: 10.1080/21655979.2022.2063649] [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] [Indexed: 11/03/2022] Open
Abstract
Metabolic reprogramming refers to the transformation of the whole metabolic network covering glycolysis and mitochondrial metabolism, which is primarily manifested as the Warburg effect and mitochondrial metabolic reprogramming. Propofol (Pro) has been testified to suppress the malignancy of diversified human cancers. Nevertheless, its role in glycolysis is still uncertain. The purpose of this study was to determine whether Pro modulated glycolysis in ovarian cancer (OC) cells. Cell proliferation, apoptosis, migration, and invasion were tested via CCK-8, flow cytometry, and Transwell assays, respectively, and glucose intake, lactic acid, and ATP production were also determined. Pro restrained glycolysis via mediating the circular RNA-zinc finger RNA-binding protein (ZFR)/microRNA (miR)-212-5p/superoxide dismutase 2 (SOD2) axis. Additionally, Pro restrained cancer cell advancement via modulating circ-ZFR/miR-212-5p/SOD2 axis. In short, Pro restrained glycolysis via mediating the circ-ZFR/miR-212-5p/SOD2 axis. These results offered a better theoretical foundation for comprehending the molecular pathology of OC and provided a novel target for OC diagnosis and treatment.
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Affiliation(s)
- DongDong Qu
- Department of Anesthesiology, Jinan Maternal and Child Health Hospital, Jinan City, Shandong Province, China
| | - Xin Zou
- Department of Anesthesiology, Qingdao Women's and Children's Hospital, Qingdao City, Shandong Province, China
| | - ZhiLin Liu
- Department of Anesthesiology, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao City, Shandong Province, China
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19
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lncRNA-DANCR Promotes Taxol Resistance of Prostate Cancer Cells through Modulating the miR-33b-5p-LDHA Axis. DISEASE MARKERS 2022; 2022:9516774. [PMID: 35571619 PMCID: PMC9096572 DOI: 10.1155/2022/9516774] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/22/2021] [Indexed: 12/18/2022]
Abstract
Prostate cancer (PCa) is one of the most common malignancies in men with high death rate worldwide. Paclitaxel (Taxol) is a widely used anticancer agent. Despite recent improvements in clinical application and research, development of drug resistance limits the efficacy of the Taxol-based chemotherapy. Previous studies revealed that the long noncoding RNA DANCR positively regulated progression of prostate cancer. However, the precise roles of DANCR in the Taxol sensitivity of PCa and the underlying molecular mechanisms remain largely unknown. Here, we report that the expressions of DANCR were significantly upregulated and miR-33b-5p were downregulated in prostate tumor specimens and cells as well as the Taxol-resistant prostate cancer cell line (PC3-TXR). Silencing DANCR or overexpressing miR-33b-5p effectively enhanced the Taxol sensitivity of PCa cells. Bioinformatics analysis, RNA pull-down assay, and luciferase assay consistently illustrated that DANCR was associated with miR-33b-5p, leading to downregulation of miR-33b-5p in PCa. Interestingly, glucose metabolism of PC3-TXR cells was remarkedly elevated. The glucose uptake, extracellular acidification rate (ECAR), and glycolysis speed-limiting enzyme expressions were significantly promoted in PC3-TXR cells. We further identified the glucose metabolism enzyme; LDHA was a direct target of miR-33b-5p in PCa cells. LDHA restoration attenuated miR-33b-5p-mediated PTX sensitization. Finally, the rescue of miR-33b-5p in DANCR-overexpressing PC3-TXR cells successfully overrode the DANCR-promoted Taxol resistance. In summary, this study uncovered biological roles and molecular mechanisms of the DANCR-promoted chemoresistance, contributing to the development of noncoding RNA-based therapeutic strategies against drug-resistant prostate cancer.
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20
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Nematode-Applied Technology for Human Tumor Microenvironment Research and Development. Curr Issues Mol Biol 2022; 44:988-997. [PMID: 35723350 PMCID: PMC8929040 DOI: 10.3390/cimb44020065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/14/2022] [Accepted: 02/17/2022] [Indexed: 11/17/2022] Open
Abstract
Nematodes, such as Caenorhabditis elegans, have been instrumental to the study of cancer. Recently, their significance as powerful cancer biodiagnostic tools has emerged, but also for mechanism analysis and drug discovery. It is expected that nematode-applied technology will facilitate research and development on the human tumor microenvironment. In the history of cancer research, which has been spurred by numerous discoveries since the last century, nematodes have been important model organisms for the discovery of cancer microenvironment. First, microRNAs (miRNAs), which are noncoding small RNAs that exert various functions to control cell differentiation, were first discovered in C. elegans and have been actively incorporated into cancer research, especially in the study of cancer genome defects. Second, the excellent sense of smell of nematodes has been applied to the diagnosis of diseases, especially refractory tumors, such as human pancreatic cancer, by sensing complex volatile compounds derived from heterogeneous cancer microenvironment, which are difficult to analyze using ordinary analytical methods. Third, a nematode model system can help evaluate invadosomes, the phenomenon of cell invasion by direct observation, which has provided a new direction for cancer research by contributing to the elucidation of complex cell–cell communications. In this cutting-edge review, we highlight milestones in cancer research history and, from a unique viewpoint, focus on recent information on the contributions of nematodes in cancer research towards precision medicine in humans.
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21
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Ginsenoside Rh2 Inhibits Glycolysis through the STAT3/c-MYC Axis in Non-Small-Cell Lung Cancer. JOURNAL OF ONCOLOGY 2021; 2021:9715154. [PMID: 34608390 PMCID: PMC8487371 DOI: 10.1155/2021/9715154] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/13/2021] [Indexed: 12/15/2022]
Abstract
Ginsenoside Rh2 (Rh2) is one of the pharmacologically active components of ginseng with an antitumor effect. However, its effect on non-small-cell lung cancer (NSCLC), especially on aerobic glycolysis, which plays a crucial role in the proliferation and progression of tumor cells, has not been characterized. Here, we demonstrated that Rh2 inhibited the proliferation and metastasis of NSCLC cells by promoting apoptosis and suppressing epithelial-mesenchymal transition, respectively. Notably, Rh2 exerted a glycolysis inhibition effect through regulating GLUT1, PKM2, and LDHA, which are key enzymes of the glycolysis process. Furthermore, the metabolic shift function of Rh2 was dependent on the STAT3/c-Myc axis in NSCLC. This novel regulatory role of Rh2 provides a new perspective for NSCLC treatment and highlights the potentiality of Rh2 to be used as a tumor energy blocker. The combination of Rh2 with an STAT3 or c-Myc inhibitor revealed a promising therapeutic approach for patients with NSCLC.
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22
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Liang W, He X, Bi J, Hu T, Sun Y. Role of reactive oxygen species in tumors based on the 'seed and soil' theory: A complex interaction (Review). Oncol Rep 2021; 46:208. [PMID: 34328200 PMCID: PMC8329912 DOI: 10.3892/or.2021.8159] [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: 03/23/2021] [Accepted: 06/24/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor microenvironment (TME) can serve as the 'soil' for the growth and survival of tumor cells and function synergically with tumor cells to mediate tumor progression and therapeutic resistance. Reactive oxygen species (ROS) is somewhat of a double‑edged sword for tumors. Accumulating evidence has reported that regulating ROS levels can serve an anti‑tumor role in the TME, including the promotion of cancer cell apoptosis, inhibition of angiogenesis, preventing immune escape, manipulating tumor metabolic reorganization and improving drug resistance. In the present review, the potential role of ROS in anti‑tumor therapy was summarized, including the possibility of directly or indirectly targeting the TME.
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Affiliation(s)
- Wei Liang
- Department of Radiation Oncology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Affiliated Hospital of Hebei Medical University, Cangzhou, Hebei 061000, P.R. China
| | - Xinying He
- Department of Radiation Oncology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Affiliated Hospital of Hebei Medical University, Cangzhou, Hebei 061000, P.R. China
| | - Jianqiang Bi
- Department of Radiation Oncology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Affiliated Hospital of Hebei Medical University, Cangzhou, Hebei 061000, P.R. China
| | - Tingting Hu
- Department of Radiation Oncology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Affiliated Hospital of Hebei Medical University, Cangzhou, Hebei 061000, P.R. China
| | - Yunchuan Sun
- Department of Radiation Oncology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Affiliated Hospital of Hebei Medical University, Cangzhou, Hebei 061000, P.R. China
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23
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Igarashi K, Nishizawa H, Saiki Y, Matsumoto M. The transcription factor BACH1 at the crossroads of cancer biology: From epithelial-mesenchymal transition to ferroptosis. J Biol Chem 2021; 297:101032. [PMID: 34339740 PMCID: PMC8387770 DOI: 10.1016/j.jbc.2021.101032] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/27/2021] [Accepted: 07/29/2021] [Indexed: 02/07/2023] Open
Abstract
The progression of cancer involves not only the gradual evolution of cells by mutations in DNA but also alterations in the gene expression induced by those mutations and input from the surrounding microenvironment. Such alterations contribute to cancer cells' abilities to reprogram metabolic pathways and undergo epithelial-to-mesenchymal transition (EMT), which facilitate the survival of cancer cells and their metastasis to other organs. Recently, BTB and CNC homology 1 (BACH1), a heme-regulated transcription factor that represses genes involved in iron and heme metabolism in normal cells, was shown to shape the metabolism and metastatic potential of cancer cells. The growing list of BACH1 target genes in cancer cells reveals that BACH1 promotes metastasis by regulating various sets of genes beyond iron metabolism. BACH1 represses the expression of genes that mediate cell–cell adhesion and oxidative phosphorylation but activates the expression of genes required for glycolysis, cell motility, and matrix protein degradation. Furthermore, BACH1 represses FOXA1 gene encoding an activator of epithelial genes and activates SNAI2 encoding a repressor of epithelial genes, forming a feedforward loop of EMT. By synthesizing these observations, we propose a “two-faced BACH1 model”, which accounts for the dynamic switching between metastasis and stress resistance along with cancer progression. We discuss here the possibility that BACH1-mediated promotion of cancer also brings increased sensitivity to iron-dependent cell death (ferroptosis) through crosstalk of BACH1 target genes, imposing programmed vulnerability upon cancer cells. We also discuss the future directions of this field, including the dynamics and plasticity of EMT.
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Affiliation(s)
- Kazuhiko Igarashi
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Hironari Nishizawa
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuriko Saiki
- Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mitsuyo Matsumoto
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan
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24
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Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases. Int J Mol Sci 2021; 22:ijms22020764. [PMID: 33466614 PMCID: PMC7828708 DOI: 10.3390/ijms22020764] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/04/2021] [Accepted: 01/11/2021] [Indexed: 02/07/2023] Open
Abstract
Glucose is an essential nutrient for every cell but its metabolic fate depends on cellular phenotype. Normally, the product of cytosolic glycolysis, pyruvate, is transported into mitochondria and irreversibly converted to acetyl coenzyme A by pyruvate dehydrogenase complex (PDC). In some pathological cells, however, pyruvate transport into the mitochondria is blocked due to the inhibition of PDC by pyruvate dehydrogenase kinase. This altered metabolism is referred to as aerobic glycolysis (Warburg effect) and is common in solid tumors and in other pathological cells. Switching from mitochondrial oxidative phosphorylation to aerobic glycolysis provides diseased cells with advantages because of the rapid production of ATP and the activation of pentose phosphate pathway (PPP) which provides nucleotides required for elevated cellular metabolism. Molecules, called glycolytics, inhibit aerobic glycolysis and convert cells to a healthier phenotype. Glycolytics often function by inhibiting hypoxia-inducible factor-1α leading to PDC disinhibition allowing for intramitochondrial conversion of pyruvate into acetyl coenzyme A. Melatonin is a glycolytic which converts diseased cells to the healthier phenotype. Herein we propose that melatonin's function as a glycolytic explains its actions in inhibiting a variety of diseases. Thus, the common denominator is melatonin's action in switching the metabolic phenotype of cells.
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