1
|
Mori MP, Lozoya OA, Brooks AM, Bortner CD, Nadalutti CA, Ryback B, Rickard BP, Overchuk M, Rizvi I, Rogasevskaia T, Huang KT, Hasan P, Hajnóczky G, Santos JH. Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling. Nat Commun 2025; 16:4029. [PMID: 40301431 PMCID: PMC12041266 DOI: 10.1038/s41467-025-59427-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 04/23/2025] [Indexed: 05/01/2025] Open
Abstract
Maintenance of the mitochondrial inner membrane potential (ΔΨm) is critical for many aspects of mitochondrial function. While ΔΨm loss and its consequences are well studied, little is known about the effects of mitochondrial hyperpolarization. In this study, we used cells deleted of ATP5IF1 (IF1), a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of increased resting ΔΨm. We found that the nuclear DNA hypermethylates when the ΔΨm is chronically high, regulating the transcription of mitochondrial, carbohydrate and lipid genes. These effects can be reversed by decreasing the ΔΨm and recapitulated in wild-type (WT) cells exposed to environmental chemicals that cause hyperpolarization. Surprisingly, phospholipid changes, but not redox or metabolic alterations, linked the ΔΨm to the epigenome. Sorted hyperpolarized WT and ovarian cancer cells naturally depleted of IF1 also showed phospholipid remodeling, indicating this as an adaptation to mitochondrial hyperpolarization. These data provide a new framework for how mitochondria can impact epigenetics and cellular biology to influence health outcomes, including through chemical exposures and in disease states.
Collapse
Affiliation(s)
- Mateus Prates Mori
- Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Durham, NC, USA
| | - Oswaldo A Lozoya
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Durham, NC, USA
| | - Ashley M Brooks
- Biostatistics and Computational Biology Branch, Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Durham, NC, USA
| | - Carl D Bortner
- Flow Cytometry Center, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Durham, NC, USA
| | - Cristina A Nadalutti
- Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Durham, NC, USA
| | - Birgitta Ryback
- Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Brittany P Rickard
- Curriculum in Toxicology & Environmental Medicine, University of North Carolina (UNC), Chapel Hill, NC, USA
| | - Marta Overchuk
- Department of Biomedical Engineering, North Carolina State University, Raleigh, NC, USA
| | - Imran Rizvi
- Department of Biomedical Engineering, North Carolina State University, Raleigh, NC, USA
- Lineberger Comprehensive Cancer Center, UNC, Chapel Hill, NC, USA
| | | | - Kai Ting Huang
- MitoCare Center, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Prottoy Hasan
- MitoCare Center, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - György Hajnóczky
- MitoCare Center, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Janine H Santos
- Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Durham, NC, USA.
| |
Collapse
|
2
|
Qiu Q, Deng H, Song P, Liu Y, Zhang M. Lactylation in Glioblastoma: A Novel Epigenetic Modifier Bridging Epigenetic Plasticity and Metabolic Reprogramming. Int J Mol Sci 2025; 26:3368. [PMID: 40244246 PMCID: PMC11989911 DOI: 10.3390/ijms26073368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/28/2025] [Accepted: 04/01/2025] [Indexed: 04/18/2025] Open
Abstract
Glioblastoma, the most common and aggressive primary malignant brain tumor, is characterized by a high rate of recurrence, disability, and lethality. Therefore, there is a pressing need to develop more effective prognostic biomarkers and treatment approaches for glioblastoma. Lactylation, an emerging form of protein post-translational modification, has been closely associated with lactate, a metabolite of glycolysis. Since the initial identification of lactylation sites in core histones in 2019, accumulating evidence has shown the critical role that lactylation plays in glioblastoma development, assessment of poor clinical prognosis, and immunosuppression, which provides a fresh angle for investigating the connection between metabolic reprogramming and epigenetic plasticity in glioblastoma cells. The objective of this paper is to present an overview of the metabolic and epigenetic roles of lactylation in the expanding field of glioblastoma research and explore the practical value of developing novel treatment plans combining targeted therapy and immunotherapy.
Collapse
Affiliation(s)
| | | | | | | | - Mengxian Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Q.Q.); (H.D.); (P.S.); (Y.L.)
| |
Collapse
|
3
|
Gu XY, Yang JL, Lai R, Zhou ZJ, Tang D, Hu L, Zhao LJ. Impact of lactate on immune cell function in the tumor microenvironment: mechanisms and therapeutic perspectives. Front Immunol 2025; 16:1563303. [PMID: 40207222 PMCID: PMC11979165 DOI: 10.3389/fimmu.2025.1563303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 03/10/2025] [Indexed: 04/11/2025] Open
Abstract
Lactate has emerged as a key regulator in the tumor microenvironment (TME), influencing both tumor progression and immune dynamics. As a byproduct of aerobic glycolysis, lactate satisfies the metabolic needs of proliferating tumor cells while reshaping the TME to facilitate immune evasion. Elevated lactate levels inhibit effector immune cells such as CD8+ T and natural killer cells, while supporting immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells, thus fostering an immunosuppressive environment. Lactate promotes epigenetic reprogramming, stabilizes hypoxia-inducible factor-1α, and activates nuclear factor kappa B, leading to further immunological dysfunction. In this review, we examined the role of lactate in metabolic reprogramming, immune suppression, and treatment resistance. We also discuss promising therapeutic strategies targeting lactate metabolism, including lactate dehydrogenase inhibitors, monocarboxylate transporter inhibitors, and TME neutralization methods, all of which can restore immune function and enhance immunotherapy outcomes. By highlighting recent advances, this review provides a theoretical foundation for integrating lactate-targeted therapies into clinical practice. We also highlight the potential synergy between these therapies and current immunotherapeutic strategies, providing new avenues for addressing TME-related challenges and improving outcomes for patients with cancer.
Collapse
Affiliation(s)
- Xuan-Yu Gu
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jia-Li Yang
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Rui Lai
- Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zheng-Jun Zhou
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Dan Tang
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Hepatobiliary and Pancreatic Surgery, Suzhou Medical College of Soochow University, Suzhou, China
| | - Long Hu
- Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, China
| | - Li-Jin Zhao
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| |
Collapse
|
4
|
Zhang S, Gong Y, Cen J, Pei Z, Wei A, Luo Z, Zhao X, Mao G, Zhang X, Xu Q, Sun M, Meng WQ. Dichloroacetate protects against sulfur mustard-induced neurotoxicity via the PDK/PDH axis and Akt/Nrf2 pathway. Free Radic Biol Med 2025; 229:154-167. [PMID: 39827920 DOI: 10.1016/j.freeradbiomed.2025.01.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/08/2025] [Accepted: 01/13/2025] [Indexed: 01/22/2025]
Abstract
Sulfur mustard (SM) is a major toxic chemical threat to public health. Mitochondrial dysfunction is considered a critical contributing factor to mustard agent-induced damage. The brain is vulnerable to SM, which can lead to various types of acute and long-term psychiatric distress after exposure, but the neurotoxic mechanisms of SM, let alone drug candidates for antidotes, are seldom studied. In this study, we employed a library of mitochondrion-targeted compounds to screen for antidotes for SM-induced neurotoxicity. Our data revealed that dichloroacetate (DCA) noticeably reduced neuronal death and helped maintain the normal morphology and function of mitochondria both in vitro and in vivo. Further experiments revealed that DCA protected neurons by inhibiting pyruvate dehydrogenase kinase (PDK), thus upregulating pyruvate dehydrogenase (PDH) and activating the protein kinase B (Akt)/Nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. Overall, our results indicated that DCA could protect against SM-induced neurotoxicity through the PDK/PDH axis and the Akt/Nrf2 pathway, suggesting that DCA is a potentially novel antidote for SM poisoning.
Collapse
Affiliation(s)
- Shanshan Zhang
- Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Yin Gong
- Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China; College of Life Sciences, Jiangxi Normal University, Nanchang, 330022, China
| | - Jinfeng Cen
- Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Zhipeng Pei
- Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Anying Wei
- Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China; College of Life Sciences, Jiangxi Normal University, Nanchang, 330022, China
| | - Zimeng Luo
- Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Xuan Zhao
- Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Guanchao Mao
- Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Xinkang Zhang
- Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Qingqiang Xu
- Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Mingxue Sun
- Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Wen-Qi Meng
- Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China.
| |
Collapse
|
5
|
Luo Y, Zhang N, Ye J, Wang Z, Zhou X, Liu J, Cai J, Li C, Chen L. Unveiling lactylation modification: A new hope for cancer treatment. Biomed Pharmacother 2025; 184:117934. [PMID: 39986235 DOI: 10.1016/j.biopha.2025.117934] [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: 12/29/2024] [Revised: 02/13/2025] [Accepted: 02/18/2025] [Indexed: 02/24/2025] Open
Abstract
This review article delves into the multifaceted role of lactylation modification in antitumor therapy, revealing the complex interplay between lactylation modification and the tumor microenvironment (TME), metabolic reprogramming, gene expression, and immunotherapy. As an emerging epigenetic modification, lactylation has a significant impact on the metabolic pathways of tumor cells, immune evasion, gene expression regulation, and sensitivity to chemotherapy drugs. Studies have shown that lactylation modification significantly alters the development and therapeutic response of tumors by affecting metabolites in the TME, immune cell functions, and signaling pathways. In the field of immunotherapy, the regulatory role of lactylation modification provides a new perspective and potential targets for tumor treatment, including modulating the sensitivity of tumors to immunotherapy by affecting the expression of immune checkpoint molecules and the infiltration of immune cells. Moreover, research progress on lactylation modification in various types of tumors indicates that it may serve as a biomarker to predict patients' responses to chemotherapy and immunotherapy. Overall, research on lactylation modification provides a theoretical foundation for the development of new tumor treatment strategies and holds promise for improving patient prognosis and quality of life. Future research will further explore the application potential of lactylation modification in tumor therapy and how to improve treatment efficacy by targeting lactylation modification.
Collapse
Affiliation(s)
- Yuxiang Luo
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Ning Zhang
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Jiarong Ye
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Zuao Wang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Xinchi Zhou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Jipeng Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Jing Cai
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Chen Li
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Institute of Orthopedics of Jiangxi Province, Nanchang, Jiangxi 330006, China; Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Disease, Jiangxi 330006, China; Institute of Minimally Invasive Orthopedics, Nanchang University, Jiangxi 330006, China.
| | - Leifeng Chen
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Precision Oncology Medicine Center,The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People's Republic of China.
| |
Collapse
|
6
|
Staudt S, Nikolka F, Perl M, Franz J, Leblay N, Yuan XK, Larrayoz M, Lozano T, Warmuth L, Fante MA, Skorpskaite A, Fei T, Bromberg M, San Martin-Uriz P, Rodriguez-Madoz JR, Ziegler-Martin K, Adil-Gholam N, Benz P, Tran Huu P, Freitag F, Riester Z, Stein-Thoeringer C, Schmitt M, Kleigrewe K, Weber J, Mangold K, Ho P, Einsele H, Prosper F, Ellmeier W, Busch D, Visekruna A, Slingerland J, Shouval R, Hiller K, Lasarte JJ, Martinez-Climent JA, Pausch P, Neri P, van den Brink M, Poeck H, Hudecek M, Luu M. Metabolization of microbial postbiotic pentanoate drives anti-cancer CAR T cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.08.19.608538. [PMID: 39314273 PMCID: PMC11418944 DOI: 10.1101/2024.08.19.608538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
The microbiome is a complex host factor and key determinant of the outcome of antibody-based and cellular immunotherapy. Its postbiotics are a blend of soluble commensal byproducts that are released into the host environment and have been associated with the regulation of immune homeostasis, particularly through impacts on epigenetics and cell signaling. In this study, we show that the postbiotic pentanoate is metabolized to citrate within the TCA cycle via both the acetyl- and succinyl-CoA entry points, a feature uniquely enabled by the chemical structure of the C5 aliphatic chain. We identified ATP-citrate lyase as the crucial factor that redirects pentanoate-derived citrate from the succinyl-CoA route to the nucleus, thereby linking metabolic output and histone acetylation. This epigenetic-metabolic crosstalk mitigated T cell exhaustion and promoted naive-like differentiation in pentanoate-programmed chimeric antigen receptor (CAR) T cells. The predictive and therapeutic potential of pentanoate was corroborated in two independent patient cohorts and three syngeneic models of CAR T adoptive therapy. Our data demonstrate that postbiotics are integrated into mitochondrial metabolism and subsequently incorporated as epigenetic imprints. This bridge between microbial and mammalian interspecies communication can ultimately impact T cell differentiation and efficacy.
Collapse
Affiliation(s)
- Sarah Staudt
- Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Fabian Nikolka
- Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany
| | - Markus Perl
- University Hospital Regensburg, Department of Internal Medicine III, Hematology & Internal Oncology, Regensburg, Germany
| | - Julia Franz
- Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Noemie Leblay
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
| | - Xiaoli-Kat Yuan
- Precision Oncology Hub, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
| | - Marta Larrayoz
- Hemato-Oncology Program, Cima Universidad de Navarra, Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Cancer Center Clinica Universidad de Navarra (CCUN), IdiSNA, Pamplona, Spain
| | - Teresa Lozano
- Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain
| | - Linda Warmuth
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany
| | - Matthias A. Fante
- University Hospital Regensburg, Department of Internal Medicine III, Hematology & Internal Oncology, Regensburg, Germany
| | - Aiste Skorpskaite
- Life Sciences Center - European Molecular Biology Laboratory (LSC-EMBL) Partnership for Genome Editing Technologies, Vilnius University - Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Teng Fei
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Maria Bromberg
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Patxi San Martin-Uriz
- Hemato-Oncology Program, Cima Universidad de Navarra, Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Cancer Center Clinica Universidad de Navarra (CCUN), IdiSNA, Pamplona, Spain
| | - Juan Roberto Rodriguez-Madoz
- Hemato-Oncology Program, Cima Universidad de Navarra, Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Cancer Center Clinica Universidad de Navarra (CCUN), IdiSNA, Pamplona, Spain
| | - Kai Ziegler-Martin
- Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Nazdar Adil-Gholam
- Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Pascal Benz
- Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Phuc Tran Huu
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, Austria
| | - Fabian Freitag
- Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Zeno Riester
- Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
- Mildred Scheel Early Career Center, University Hospital of Würzburg, Würzburg, Germany
| | | | - Michael Schmitt
- Department of Hematology, Oncology and Rheumatology, University Clinic Heidelberg, Heidelberg, Germany
| | - Karin Kleigrewe
- Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), Technical University of Munich, Freising, Germany
| | - Justus Weber
- Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Kira Mangold
- Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
- Institute for Medical Microbiology and Hygiene, Philipps-University Marburg, Marburg, Germany
| | - Patrick Ho
- Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Hermann Einsele
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
- National Center for Tumor Therapy (NCT WERA), Würzburg, Germany
| | - Felipe Prosper
- Hematology and Cell Therapy Department, Clinica Universidad de Navarra (CUN), Hemato-Oncology Program, Cima Universidad de Navarra. Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Cancer Center Clinica Universidad de Navarra (CCUN), IdiSNA, Pamplona, Spain
| | - Wilfried Ellmeier
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, Austria
| | - Dirk Busch
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany
| | - Alexander Visekruna
- Institute for Medical Microbiology and Hygiene, Philipps-University Marburg, Marburg, Germany
| | | | - Roni Shouval
- Adult Bone Marrow Transplantation Service and Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, New York, New York
| | - Karsten Hiller
- Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany
| | - Juan Jose Lasarte
- Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain
| | - Jose Angel Martinez-Climent
- Hemato-Oncology Program, Cima Universidad de Navarra, Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Cancer Center Clinica Universidad de Navarra (CCUN), IdiSNA, Pamplona, Spain
| | - Patrick Pausch
- Life Sciences Center - European Molecular Biology Laboratory (LSC-EMBL) Partnership for Genome Editing Technologies, Vilnius University - Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Paola Neri
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
| | | | - Hendrik Poeck
- University Hospital Regensburg, Department of Internal Medicine III, Hematology & Internal Oncology, Regensburg, Germany
- Leibniz Institute for Immunotherapy (LIT), Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), Regensburg & Würzburg, Germany
| | - Michael Hudecek
- Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
- National Center for Tumor Therapy (NCT WERA), Würzburg, Germany
- Bavarian Cancer Research Center (BZKF), Regensburg & Würzburg, Germany
| | - Maik Luu
- Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
- National Center for Tumor Therapy (NCT WERA), Würzburg, Germany
- Bavarian Cancer Research Center (BZKF), Regensburg & Würzburg, Germany
| |
Collapse
|
7
|
Blažič A, Guinard M, Leskovar T, O'Connor RP, Rems L. Long-term changes in transmembrane voltage after electroporation are governed by the interplay between nonselective leak current and ion channel activation. Bioelectrochemistry 2025; 161:108802. [PMID: 39243733 DOI: 10.1016/j.bioelechem.2024.108802] [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: 06/24/2024] [Revised: 08/14/2024] [Accepted: 08/26/2024] [Indexed: 09/09/2024]
Abstract
Electroporation causes a temporal increase in cell membrane permeability and leads to prolonged changes in transmembrane voltage (TMV) in both excitable and non-excitable cells. However, the mechanisms of these TMV changes remain to be fully elucidated. To this end, we monitored TMV over 30 min after exposing two different cell lines to a single 100 µs electroporation pulse using the FLIPR Membrane Potential dye. In CHO-K1 cells, which express very low levels of endogenous ion channels, membrane depolarization following pulse exposure could be explained by nonselective leak current, which persists until the membrane reseals, enabling the cells to recover their resting TMV. In U-87 MG cells, which express many different ion channels, we unexpectedly observed membrane hyperpolarization following the initial depolarization phase, but only at 33 °C and not at 25 °C. We developed a theoretical model, supported by experiments with ion channel inhibitors, which indicated that hyperpolarization could largely be attributed to the activation of calcium-activated potassium channels. Ion channel activation, coupled with changes in TMV and intracellular calcium, participates in various physiological processes, including cell proliferation, differentiation, migration, and apoptosis. Therefore, our study suggests that ion channels could present a potential target for influencing the biological response after electroporation.
Collapse
Affiliation(s)
- Anja Blažič
- University of Ljubljana, Faculty of Electrical Engineering, SI-1000 Ljubljana, Slovenia
| | - Manon Guinard
- University of Ljubljana, Faculty of Electrical Engineering, SI-1000 Ljubljana, Slovenia
| | - Tomaž Leskovar
- University of Ljubljana, Faculty of Electrical Engineering, SI-1000 Ljubljana, Slovenia
| | - Rodney P O'Connor
- Mines Saint-Etienne, Centre CMP, Département BEL, F-13541 Gardanne, France
| | - Lea Rems
- University of Ljubljana, Faculty of Electrical Engineering, SI-1000 Ljubljana, Slovenia.
| |
Collapse
|
8
|
Ma M, Zhang Y, Pu K, Tang W. Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity. Chem Soc Rev 2025; 54:653-714. [PMID: 39620588 DOI: 10.1039/d4cs00679h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2025]
Abstract
Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.
Collapse
Affiliation(s)
- Muye Ma
- Department of Diagnostic Radiology, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.
| | - Yongliang Zhang
- Department of Microbiology and Immunology, Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Dr 2, Singapore, 117545, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, 28 Medical Dr, Singapore, 117597, Singapore
| | - Kanyi Pu
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 70 Nanyang Drive, Singapore, 637457, Singapore.
- Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore, 636921, Singapore
| | - Wei Tang
- Department of Diagnostic Radiology, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.
- Department of Pharmacy and Pharmaceutic Sciences, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore
| |
Collapse
|
9
|
Dhiman A, Rana D, Benival D, Garkhal K. Comprehensive insights into glioblastoma multiforme: drug delivery challenges and multimodal treatment strategies. Ther Deliv 2025; 16:87-115. [PMID: 39445563 PMCID: PMC11703381 DOI: 10.1080/20415990.2024.2415281] [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: 05/06/2024] [Accepted: 10/08/2024] [Indexed: 10/25/2024] Open
Abstract
Glioblastoma multiforme (GBM) is one of the most common and malignant brain tumors, with a high prevalence in elderly population. Most chemotherapeutic agents fail to reach the tumor site due to various challenges. However, smart nanocarriers have demonstrated excellent drug-loading capabilities, enabling them to cross the blood brain tumor barrier for the GBM treatment. Surface modification of nanocarriers has significantly enhanced their potential for targeting therapeutics. Moreover, recent innovations in drug therapies, such as the incorporation of theranostic agents in nanocarriers and antibody-drug conjugates, have offered newer insights for both diagnosis and treatment. This review focuses on recent advances in new therapeutic interventions for GBM, with an emphasis on the nanotheranostics systems to maximize therapeutic and diagnostic outcomes.
Collapse
Affiliation(s)
- Ashish Dhiman
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research-Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Dhwani Rana
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research-Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Derajram Benival
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research-Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Kalpna Garkhal
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research-Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| |
Collapse
|
10
|
Dias AS, Almeida CR, Helguero L, Duarte IF. Antitumoral Activity and Metabolic Signatures of Dichloroacetate, 6-Aminonicotinamide and Etomoxir in Breast-Tumor-Educated Macrophages. J Proteome Res 2024; 23:5498-5510. [PMID: 39475502 DOI: 10.1021/acs.jproteome.4c00654] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
Pharmacological targeting of metabolic pathways represents an appealing strategy to selectively kill cancer cells while promoting antitumor functions of stromal cells. In this study, we assessed the effectiveness of 13 metabolic drugs (MDs) in steering in vitro generated breast tumor-educated macrophages (TEMs) toward an antitumoral phenotype. For that, the production of vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNF-α), two important regulators of tumor progression, was evaluated. Notably, dichloroacetate (DCA), 6-aminonicotinamide (6-AN), and etomoxir decreased VEGF production and enhanced TNF-α release. Hence, we further clarified their impact on TEM metabolism using an untargeted NMR-based metabolomics approach. DCA downregulated glycolysis and enhanced the utilization of extracellular substrates like lactate while reconfiguring lipid metabolism. Several DCA-induced changes significantly correlated with heightened TNF-α production in response to pro-inflammatory stimulation. The inhibition of the pentose phosphate pathway by 6-AN was accompanied by enhanced glutaminolysis, which correlated with a decreased level of VEGF production. In etomoxir-treated TEM, inhibition of fatty acid oxidation was compensated through upregulation of glycolysis, catabolism of intracellular amino acids, and consumption of extracellular branched chain alpha-ketoacids (BCKA) and citrate. Overall, our results offer a comprehensive view of the metabolic signature of each MD in breast TEM and highlight putative correlations with phenotypic effects.
Collapse
Affiliation(s)
- Ana S Dias
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
- iBiMED - Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Catarina R Almeida
- iBiMED - Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Luisa Helguero
- iBiMED - Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Iola F Duarte
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| |
Collapse
|
11
|
Wang S, Huang T, Wu Q, Yuan H, Wu X, Yuan F, Duan T, Taori S, Zhao Y, Snyder NW, Placantonakis DG, Rich JN. Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation. J Clin Invest 2024; 134:e176851. [PMID: 39545414 PMCID: PMC11563687 DOI: 10.1172/jci176851] [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: 10/25/2023] [Accepted: 09/25/2024] [Indexed: 11/17/2024] Open
Abstract
Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a "don't eat me" signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.
Collapse
Affiliation(s)
- Shuai Wang
- Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Department of Neurosurgery and Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, New York, USA
| | - Tengfei Huang
- Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Qiulian Wu
- Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Huairui Yuan
- Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Xujia Wu
- Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Fanen Yuan
- Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Tingting Duan
- Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Suchet Taori
- School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Yingming Zhao
- Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA
| | - Nathaniel W. Snyder
- Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Dimitris G. Placantonakis
- Department of Neurosurgery and Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, New York, USA
| | - Jeremy N. Rich
- Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| |
Collapse
|
12
|
Sánchez-Castillo A, Savelkouls KG, Baldini A, Hounjet J, Sonveaux P, Verstraete P, De Keersmaecker K, Dewaele B, Björkblom B, Melin B, Wu WY, Sjöberg RL, Rouschop KMA, Broen MPG, Vooijs M, Kampen KR. Sertraline/chloroquine combination therapy to target hypoxic and immunosuppressive serine/glycine synthesis-dependent glioblastomas. Oncogenesis 2024; 13:39. [PMID: 39537592 PMCID: PMC11561346 DOI: 10.1038/s41389-024-00540-3] [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: 03/25/2024] [Revised: 10/29/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024] Open
Abstract
The serine/glycine (ser/gly) synthesis pathway branches from glycolysis and is hyperactivated in approximately 30% of cancers. In ~13% of glioblastoma cases, we observed frequent amplifications and rare mutations in the gene encoding the enzyme PSPH, which catalyzes the last step in the synthesis of serine. This urged us to unveil the relevance of PSPH genetic alterations and subsequent ser/gly metabolism deregulation in the pathogenesis of glioblastoma. Primary glioblastoma cells overexpressing PSPH and PSPHV116I showed an increased clonogenic capacity, cell proliferation, and migration, supported by elevated nucleotide synthesis and utilization of reductive NAD(P). We previously identified sertraline as an inhibitor of ser/gly synthesis and explored its efficacy at suboptimal dosages in combination with the clinically pretested chloroquine to target ser/glyhigh glioblastoma models. Interestingly, ser/glyhigh glioblastomas, including PSPHamp and PSPHV116I, displayed selective synergistic inhibition of proliferation in response to combination therapy. PSPH knockdown severely affected ser/glyhigh glioblastoma clonogenicity and proliferation, while simultaneously increasing its sensitivity to chloroquine treatment. Metabolite landscaping revealed that sertraline/chloroquine combination treatment blocks NADH and ATP generation and restricts nucleotide synthesis, thereby inhibiting glioblastoma proliferation. Our previous studies highlight ser/glyhigh cancer cell modulation of its microenvironment at the level of immune suppression. To this end, high PSPH expression predicts poor immune checkpoint therapy responses in glioblastoma patients. Interestingly, we show that PSPH amplifications in glioblastoma facilitate the expression of immune suppressor galectin-1, which can be inhibited by sertraline treatment. Collectively, we revealed that ser/glyhigh glioblastomas are characterized by enhanced clonogenicity, migration, and suppression of the immune system, which could be tackled using combined sertraline/chloroquine treatment, revealing novel therapeutic opportunities for this subgroup of GBM patients.
Collapse
Affiliation(s)
- Anaís Sánchez-Castillo
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Kim G Savelkouls
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Alessandra Baldini
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Judith Hounjet
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Pierre Sonveaux
- Pole of Pharmacology, Institut de Recherche Experimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
- WEL Research Institute, WELBIO Department, Wavre, Belgium
| | - Paulien Verstraete
- Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Kim De Keersmaecker
- Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Barbara Dewaele
- Center for Human Genetics, Laboratory for Genetics of Malignant Disorders, University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | | | - Beatrice Melin
- Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden
| | - Wendy Y Wu
- Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden
| | - Rickard L Sjöberg
- Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden
| | - Kasper M A Rouschop
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Martijn P G Broen
- Department of Neurology, GROW School for Oncology and Reproduction, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Marc Vooijs
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Kim R Kampen
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands.
- Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
| |
Collapse
|
13
|
Trejo-Solís C, Serrano-García N, Castillo-Rodríguez RA, Robledo-Cadena DX, Jimenez-Farfan D, Marín-Hernández Á, Silva-Adaya D, Rodríguez-Pérez CE, Gallardo-Pérez JC. Metabolic dysregulation of tricarboxylic acid cycle and oxidative phosphorylation in glioblastoma. Rev Neurosci 2024; 35:813-838. [PMID: 38841811 DOI: 10.1515/revneuro-2024-0054] [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: 04/16/2024] [Accepted: 05/21/2024] [Indexed: 06/07/2024]
Abstract
Glioblastoma multiforme (GBM) exhibits genetic alterations that induce the deregulation of oncogenic pathways, thus promoting metabolic adaptation. The modulation of metabolic enzyme activities is necessary to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates essential for fulfilling the biosynthetic needs of glioma cells. Moreover, the TCA cycle produces intermediates that play important roles in the metabolism of glucose, fatty acids, or non-essential amino acids, and act as signaling molecules associated with the activation of oncogenic pathways, transcriptional changes, and epigenetic modifications. In this review, we aim to explore how dysregulated metabolic enzymes from the TCA cycle and oxidative phosphorylation, along with their metabolites, modulate both catabolic and anabolic metabolic pathways, as well as pro-oncogenic signaling pathways, transcriptional changes, and epigenetic modifications in GBM cells, contributing to the formation, survival, growth, and invasion of glioma cells. Additionally, we discuss promising therapeutic strategies targeting key players in metabolic regulation. Therefore, understanding metabolic reprogramming is necessary to fully comprehend the biology of malignant gliomas and significantly improve patient survival.
Collapse
Affiliation(s)
- Cristina Trejo-Solís
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Laboratorio de Neurobiología Molecular y Celular, Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico
| | - Norma Serrano-García
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Laboratorio de Neurobiología Molecular y Celular, Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico
| | - Rosa Angelica Castillo-Rodríguez
- CICATA Unidad Morelos, Instituto Politécnico Nacional, Boulevard de la Tecnología, 1036 Z-1, P 2/2, Atlacholoaya, Xochitepec 62790, Mexico
| | - Diana Xochiquetzal Robledo-Cadena
- Departamento de Fisiopatología Cardio-Renal, Departamento de Bioquímica, Instituto Nacional de Cardiología, Ciudad de México 14080, Mexico
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Coyoacán, 04510, Ciudad de México, Mexico
| | - Dolores Jimenez-Farfan
- Laboratorio de Inmunología, División de Estudios de Posgrado e Investigación, Facultad de Odontología, Universidad Nacional Autónoma de México, Ciudad de Mexico 04510, Mexico
| | - Álvaro Marín-Hernández
- Departamento de Fisiopatología Cardio-Renal, Departamento de Bioquímica, Instituto Nacional de Cardiología, Ciudad de México 14080, Mexico
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Coyoacán, 04510, Ciudad de México, Mexico
| | - Daniela Silva-Adaya
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Laboratorio de Neurobiología Molecular y Celular, Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico
| | - Citlali Ekaterina Rodríguez-Pérez
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Laboratorio de Neurobiología Molecular y Celular, Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico
| | - Juan Carlos Gallardo-Pérez
- Departamento de Fisiopatología Cardio-Renal, Departamento de Bioquímica, Instituto Nacional de Cardiología, Ciudad de México 14080, Mexico
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Coyoacán, 04510, Ciudad de México, Mexico
| |
Collapse
|
14
|
Wang N, Yuan Y, Hu T, Xu H, Piao H. Metabolism: an important player in glioma survival and development. Discov Oncol 2024; 15:577. [PMID: 39436434 PMCID: PMC11496451 DOI: 10.1007/s12672-024-01402-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 09/26/2024] [Indexed: 10/23/2024] Open
Abstract
Gliomas are malignant tumors originating from both neuroglial cells and neural stem cells. The involvement of neural stem cells contributes to the tumor's heterogeneity, affecting its metabolic features, development, and response to therapy. This review provides a brief introduction to the importance of metabolism in gliomas before systematically categorizing them into specific groups based on their histological and molecular genetic markers. Metabolism plays a critical role in glioma biology, as tumor cells rely heavily on altered metabolic pathways to support their rapid growth, survival, and progression. Dysregulated metabolic processes, involving carbohydrates, lipids, and amino acids not only fuel tumor development but also contribute to therapy resistance and metastatic potential. By understanding these metabolic changes, key intervention points, such as mutations in genes like RTK, EGFR, RAS, and IDH can be identified, paving the way for novel therapeutic strategies. This review emphasizes the connection between metabolic pathways and clinical challenges, offering actionable insights for future research and therapeutic development in gliomas.
Collapse
Affiliation(s)
- Ning Wang
- Department of Neurosurgery, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Shenyang, Dadong, 110042, P R China
- Institute of Cancer Medicine, Dalian University of Technology, No.2 Linggong Road, Dalian, Ganjingzi, 116024, P R China
| | - Yiru Yuan
- Department of Neurosurgery, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Shenyang, Dadong, 110042, P R China
- Institute of Cancer Medicine, Dalian University of Technology, No.2 Linggong Road, Dalian, Ganjingzi, 116024, P R China
| | - Tianhao Hu
- Department of Neurosurgery, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Shenyang, Dadong, 110042, P R China
- Institute of Cancer Medicine, Dalian University of Technology, No.2 Linggong Road, Dalian, Ganjingzi, 116024, P R China
| | - Huizhe Xu
- Institute of Cancer Medicine, Dalian University of Technology, No.2 Linggong Road, Dalian, Ganjingzi, 116024, P R China.
- Central Laboratory, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Shenyang, Liaoning Province, 110042, P R China.
| | - Haozhe Piao
- Department of Neurosurgery, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Shenyang, Dadong, 110042, P R China.
- Institute of Cancer Medicine, Dalian University of Technology, No.2 Linggong Road, Dalian, Ganjingzi, 116024, P R China.
| |
Collapse
|
15
|
Köse SG, Güleç Taşkıran AE. Mechanisms of drug resistance in nutrient-depleted colorectal cancer cells: insights into lysosomal and mitochondrial drug sequestration. Biol Open 2024; 13:bio060448. [PMID: 39445740 PMCID: PMC11554266 DOI: 10.1242/bio.060448] [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] [Indexed: 10/25/2024] Open
Abstract
This Review delves into the mechanisms behind drug resistance in colorectal cancer (CRC), particularly examining the role of nutrient depletion and its contribution to multidrug resistance (MDR). The study highlights metabolic adaptations of cancer cells as well as metabolic adaptations of cancer cells under low nutrient availability, including shifts in glycolysis and lipid metabolism. It emphasizes the significance of MDR1 and its encoded efflux transporter, P-glycoprotein (P-gp/B1), in mediating drug resistance and how pathways such as HIF1α, AKT, and mTOR influence the expression of P-gp/B1 under limited nutrient availability. Additionally, the Review explores the dual roles of autophagy in drug sensitivity and resistance under nutrient limited conditions. It further investigates the involvement of lysosomes and mitochondria, focusing on their roles in drug sequestration and the challenges posed by lysosomal entrapment facilitated by non-enzymatic processes and ABC transporters like P-gp/B1. Finally, the Review underscores the importance of understanding the interplay between drug sequestration, lysosomal functions, nutrient depletion, and MDR1 gene modulation. It suggests innovative strategies, including structural modifications and nanotechnology, as promising approaches to overcoming drug resistance in cancer therapy.
Collapse
Affiliation(s)
- Serra Gülse Köse
- Molecular Biology and Genetics Department, Baskent University, Ankara 06790, Turkey
| | | |
Collapse
|
16
|
Koltai T, Fliegel L. Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts. Pharmaceuticals (Basel) 2024; 17:744. [PMID: 38931411 PMCID: PMC11206832 DOI: 10.3390/ph17060744] [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: 03/28/2024] [Revised: 05/23/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024] Open
Abstract
Rarely has a chemical elicited as much controversy as dichloroacetate (DCA). DCA was initially considered a dangerous toxic industrial waste product, then a potential treatment for lactic acidosis. However, the main controversies started in 2008 when DCA was found to have anti-cancer effects on experimental animals. These publications showed contradictory results in vivo and in vitro such that a thorough consideration of this compound's in cancer is merited. Despite 50 years of experimentation, DCA's future in therapeutics is uncertain. Without adequate clinical trials and health authorities' approval, DCA has been introduced in off-label cancer treatments in alternative medicine clinics in Canada, Germany, and other European countries. The lack of well-planned clinical trials and its use by people without medical training has discouraged consideration by the scientific community. There are few thorough clinical studies of DCA, and many publications are individual case reports. Case reports of DCA's benefits against cancer have been increasing recently. Furthermore, it has been shown that DCA synergizes with conventional treatments and other repurposable drugs. Beyond the classic DCA target, pyruvate dehydrogenase kinase, new target molecules have also been recently discovered. These findings have renewed interest in DCA. This paper explores whether existing evidence justifies further research on DCA for cancer treatment and it explores the role DCA may play in it.
Collapse
Affiliation(s)
- Tomas Koltai
- Hospital del Centro Gallego de Buenos Aires, Buenos Aires 2199, Argentina
| | - Larry Fliegel
- Department of Biochemistry, University Alberta, Edmonton, AB T6G 2H7, Canada;
| |
Collapse
|
17
|
Cherfan C, Chebly A, Rezvani HR, Beylot-Barry M, Chevret E. Delving into the Metabolism of Sézary Cells: A Brief Review. Genes (Basel) 2024; 15:635. [PMID: 38790264 PMCID: PMC11121102 DOI: 10.3390/genes15050635] [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: 03/29/2024] [Revised: 05/14/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
Primary cutaneous lymphomas (PCLs) are a heterogeneous group of lymphoproliferative disorders caused by the accumulation of neoplastic T or B lymphocytes in the skin. Sézary syndrome (SS) is an aggressive and rare form of cutaneous T cell lymphoma (CTCL) characterized by an erythroderma and the presence of atypical cerebriform T cells named Sézary cells in skin and blood. Most of the available treatments for SS are not curative, which means there is an urgent need for the development of novel efficient therapies. Recently, targeting cancer metabolism has emerged as a promising strategy for cancer therapy. This is due to the accumulating evidence that metabolic reprogramming highly contributes to tumor progression. Genes play a pivotal role in regulating metabolic processes, and alterations in these genes can disrupt the delicate balance of metabolic pathways, potentially contributing to cancer development. In this review, we discuss the importance of targeting energy metabolism in tumors and the currently available data on the metabolism of Sézary cells, paving the way for potential new therapeutic approaches aiming to improve clinical outcomes for patients suffering from SS.
Collapse
Affiliation(s)
- Carel Cherfan
- BRIC, BoRdeaux Institute of onCology, UMR 1312, Inserm, Université de Bordeaux, 33000 Bordeaux, France; (C.C.); (H.R.R.); (M.B.-B.)
| | - Alain Chebly
- Center Jacques Loiselet for Medical Genetics and Genomics (CGGM), Faculty of Medicine, Saint Joseph University, Beirut P.O. Box 17-5208, Lebanon;
| | - Hamid Reza Rezvani
- BRIC, BoRdeaux Institute of onCology, UMR 1312, Inserm, Université de Bordeaux, 33000 Bordeaux, France; (C.C.); (H.R.R.); (M.B.-B.)
| | - Marie Beylot-Barry
- BRIC, BoRdeaux Institute of onCology, UMR 1312, Inserm, Université de Bordeaux, 33000 Bordeaux, France; (C.C.); (H.R.R.); (M.B.-B.)
- Dermatology Department, Centre Hospitalier Universitaire de Bordeaux, 33075 Bordeaux, France
| | - Edith Chevret
- BRIC, BoRdeaux Institute of onCology, UMR 1312, Inserm, Université de Bordeaux, 33000 Bordeaux, France; (C.C.); (H.R.R.); (M.B.-B.)
| |
Collapse
|
18
|
Lin H, Liu C, Hu A, Zhang D, Yang H, Mao Y. Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives. J Hematol Oncol 2024; 17:31. [PMID: 38720342 PMCID: PMC11077829 DOI: 10.1186/s13045-024-01544-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 04/10/2024] [Indexed: 05/12/2024] Open
Abstract
Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite the established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, and the exploration of emerging modalities such as immunotherapy and integration of medicine and engineering technology therapy, the efficacy of these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny of the inhibitory and immunosuppressive milieu within GBM has underscored the significance of cellular constituents of the GBM microenvironment and their interactions with malignant cells and neurons. Novel immune and targeted therapy strategies have emerged, offering promising avenues for advancing GBM treatment. One pivotal mechanism orchestrating immunosuppression in GBM involves the aggregation of myeloid-derived suppressor cells (MDSCs), glioma-associated macrophage/microglia (GAM), and regulatory T cells (Tregs). Among these, MDSCs, though constituting a minority (4-8%) of CD45+ cells in GBM, play a central component in fostering immune evasion and propelling tumor progression, angiogenesis, invasion, and metastasis. MDSCs deploy intricate immunosuppressive mechanisms that adapt to the dynamic tumor microenvironment (TME). Understanding the interplay between GBM and MDSCs provides a compelling basis for therapeutic interventions. This review seeks to elucidate the immune regulatory mechanisms inherent in the GBM microenvironment, explore existing therapeutic targets, and consolidate recent insights into MDSC induction and their contribution to GBM immunosuppression. Additionally, the review comprehensively surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. Through the synergistic integration of immunotherapy with other therapeutic modalities, this approach can establish a multidisciplinary, multi-target paradigm, ultimately improving the prognosis and quality of life in patients with GBM.
Collapse
Affiliation(s)
- Hao Lin
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Chaxian Liu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Ankang Hu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Duanwu Zhang
- Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, People's Republic of China.
| | - Hui Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
- Institute for Translational Brain Research, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
| |
Collapse
|
19
|
Liu X, Li J, Huang Q, Jin M, Huang G. Ginsenoside Rh2 shifts tumor metabolism from aerobic glycolysis to oxidative phosphorylation through regulating the HIF1-α/PDK4 axis in non-small cell lung cancer. Mol Med 2024; 30:56. [PMID: 38671369 PMCID: PMC11055298 DOI: 10.1186/s10020-024-00813-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 03/18/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND Ginsenoside Rh2 (G-Rh2), a steroidal compound extracted from roots of ginseng, has been extensively studied in tumor therapy. However, its specific regulatory mechanism in non-small cell lung cancer (NSCLC) is not well understood. Pyruvate dehydrogenase kinase 4 (PDK4), a central regulator of cellular energy metabolism, is highly expressed in various malignant tumors. We investigated the impact of G-Rh2 on the malignant progression of NSCLC and how it regulated PDK4 to influence tumor aerobic glycolysis and mitochondrial function. METHOD We examined the inhibitory effect of G-Rh2 on NSCLC through I proliferation assay, migration assay and flow cytometry in vitro. Subsequently, we verified the ability of G-Rh2 to inhibit tumor growth and metastasis by constructing subcutaneous tumor and metastasis models in nude mice. Proteomics analysis was conducted to analyze the action pathways of G-Rh2. Additionally, we assessed glycolysis and mitochondrial function using seahorse, PET-CT, Western blot, and RT-qPCR. RESULT Treatment with G-Rh2 significantly inhibited tumor proliferation and migration ability both in vitro and in vivo. Furthermore, G-Rh2 inhibited the tumor's aerobic glycolytic capacity, including glucose uptake and lactate production, through the HIF1-α/PDK4 pathway. Overexpression of PDK4 demonstrated that G-Rh2 targeted the inhibition of PDK4 expression, thereby restoring mitochondrial function, promoting reactive oxygen species (ROS) accumulation, and inducing apoptosis. When combined with sodium dichloroacetate, a PDK inhibitor, it complemented the inhibitory capacity of PDKs, acting synergistically as a detoxifier. CONCLUSION G-Rh2 could target and down-regulate the expression of HIF-1α, resulting in decreased expression of glycolytic enzymes and inhibition of aerobic glycolysis in tumors. Additionally, by directly targeting mitochondrial PDK, it elevated mitochondrial oxidative phosphorylation and enhanced ROS accumulation, thereby promoting tumor cells to undergo normal apoptotic processes.
Collapse
Affiliation(s)
- Xiyu Liu
- Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, P.R. China
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Road, Pudong New Area, 201318, Shanghai, China
| | - Jingjing Li
- Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, P.R. China
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Road, Pudong New Area, 201318, Shanghai, China
| | - Qingqing Huang
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Road, Pudong New Area, 201318, Shanghai, China.
| | - Mingming Jin
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Road, Pudong New Area, 201318, Shanghai, China.
| | - Gang Huang
- Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, P.R. China.
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Road, Pudong New Area, 201318, Shanghai, China.
| |
Collapse
|
20
|
Trejo-Solís C, Castillo-Rodríguez RA, Serrano-García N, Silva-Adaya D, Vargas-Cruz S, Chávez-Cortéz EG, Gallardo-Pérez JC, Zavala-Vega S, Cruz-Salgado A, Magaña-Maldonado R. Metabolic Roles of HIF1, c-Myc, and p53 in Glioma Cells. Metabolites 2024; 14:249. [PMID: 38786726 PMCID: PMC11122955 DOI: 10.3390/metabo14050249] [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: 04/01/2024] [Revised: 04/18/2024] [Accepted: 04/20/2024] [Indexed: 05/25/2024] Open
Abstract
The metabolic reprogramming that promotes tumorigenesis in glioblastoma is induced by dynamic alterations in the hypoxic tumor microenvironment, as well as in transcriptional and signaling networks, which result in changes in global genetic expression. The signaling pathways PI3K/AKT/mTOR and RAS/RAF/MEK/ERK stimulate cell metabolism, either directly or indirectly, by modulating the transcriptional factors p53, HIF1, and c-Myc. The overexpression of HIF1 and c-Myc, master regulators of cellular metabolism, is a key contributor to the synthesis of bioenergetic molecules that mediate glioma cell transformation, proliferation, survival, migration, and invasion by modifying the transcription levels of key gene groups involved in metabolism. Meanwhile, the tumor-suppressing protein p53, which negatively regulates HIF1 and c-Myc, is often lost in glioblastoma. Alterations in this triad of transcriptional factors induce a metabolic shift in glioma cells that allows them to adapt and survive changes such as mutations, hypoxia, acidosis, the presence of reactive oxygen species, and nutrient deprivation, by modulating the activity and expression of signaling molecules, enzymes, metabolites, transporters, and regulators involved in glycolysis and glutamine metabolism, the pentose phosphate cycle, the tricarboxylic acid cycle, and oxidative phosphorylation, as well as the synthesis and degradation of fatty acids and nucleic acids. This review summarizes our current knowledge on the role of HIF1, c-Myc, and p53 in the genic regulatory network for metabolism in glioma cells, as well as potential therapeutic inhibitors of these factors.
Collapse
Affiliation(s)
- Cristina Trejo-Solís
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Departamento de Neurofisiología, Laboratorio Clínico y Banco de Sangre y Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (N.S.-G.); (D.S.-A.); (S.Z.-V.)
| | | | - Norma Serrano-García
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Departamento de Neurofisiología, Laboratorio Clínico y Banco de Sangre y Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (N.S.-G.); (D.S.-A.); (S.Z.-V.)
| | - Daniela Silva-Adaya
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Departamento de Neurofisiología, Laboratorio Clínico y Banco de Sangre y Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (N.S.-G.); (D.S.-A.); (S.Z.-V.)
- Centro de Investigación Sobre el Envejecimiento, Centro de Investigación y de Estudios Avanzados (CIE-CINVESTAV), Ciudad de Mexico 14330, Mexico
| | - Salvador Vargas-Cruz
- Departamento de Cirugía, Hospital Ángeles del Pedregal, Camino a Sta. Teresa, Ciudad de Mexico 10700, Mexico;
| | | | - Juan Carlos Gallardo-Pérez
- Departamento de Fisiopatología Cardio-Renal, Departamento de Bioquímica, Instituto Nacional de Cardiología, Ciudad de Mexico 14080, Mexico;
| | - Sergio Zavala-Vega
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Departamento de Neurofisiología, Laboratorio Clínico y Banco de Sangre y Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (N.S.-G.); (D.S.-A.); (S.Z.-V.)
| | - Arturo Cruz-Salgado
- Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca 62100, Mexico;
| | - Roxana Magaña-Maldonado
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Departamento de Neurofisiología, Laboratorio Clínico y Banco de Sangre y Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (N.S.-G.); (D.S.-A.); (S.Z.-V.)
| |
Collapse
|
21
|
Wang Z, Xu T, Sun Y, Zhang X, Wang X. AMPK/PGC-1α and p53 modulate VDAC1 expression mediated by reduced ATP level and metabolic oxidative stress in neuronal cells. Acta Biochim Biophys Sin (Shanghai) 2024; 56:162-173. [PMID: 38298056 PMCID: PMC10984866 DOI: 10.3724/abbs.2024012] [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: 06/08/2023] [Accepted: 09/12/2023] [Indexed: 02/02/2024] Open
Abstract
Voltage-dependent anion channel 1 (VDAC1) is a pore protein located in the outer mitochondrial membrane. Its channel gating mediates mitochondrial respiration and cell metabolism, and it has been identified as a critical modulator of mitochondria-mediated apoptosis. In many diseases characterized by mitochondrial dysfunction, such as cancer and neurodegenerative diseases, VDAC1 is considered a promising potential therapeutic target. However, there is limited research on the regulatory factors involved in VDAC1 protein expression in both normal and pathological states. In this study, we find that VDAC1 protein expression is up-regulated in various neuronal cell lines in response to intracellular metabolic and oxidative stress. We further demonstrate that VDAC1 expression is modulated by intracellular ATP level. Through the use of pharmacological agonists and inhibitors and small interfering RNA (siRNA), we reveal that the AMPK/PGC-1α signaling pathway is involved in regulating VDAC1 expression. Additionally, based on bioinformatics predictions and biochemical verification, we identify p53 as a potential transcription factor that regulates VDAC1 promoter activity during metabolic oxidative stress. Our findings suggest that VDAC1 expression is regulated by the AMPK/PGC-1α and p53 pathways, which contributes to the maintenance of stress adaptation and apoptotic homeostasis in neuronal cells.
Collapse
Affiliation(s)
- Zhitong Wang
- State Key Laboratory of Bioactive Substances and Functions of Natural MedicinesDepartment of PharmacologyInstitute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100050China
- Department of PharmacyPeking University Third HospitalInstitute for Drug EvaluationPeking University Health Science CenterTherapeutic Drug Monitoring and Clinical Toxicology CenterPeking UniversityBeijing100191China
| | - Tingting Xu
- State Key Laboratory of Bioactive Substances and Functions of Natural MedicinesDepartment of PharmacologyInstitute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100050China
| | - Yingni Sun
- State Key Laboratory of Bioactive Substances and Functions of Natural MedicinesDepartment of PharmacologyInstitute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100050China
| | - Xiang Zhang
- State Key Laboratory of Bioactive Substances and Functions of Natural MedicinesDepartment of PharmacologyInstitute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100050China
| | - Xiaoliang Wang
- State Key Laboratory of Bioactive Substances and Functions of Natural MedicinesDepartment of PharmacologyInstitute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100050China
| |
Collapse
|
22
|
Nath S, Balling R. The Warburg Effect Reinterpreted 100 yr on: A First-Principles Stoichiometric Analysis and Interpretation from the Perspective of ATP Metabolism in Cancer Cells. FUNCTION 2024; 5:zqae008. [PMID: 38706962 PMCID: PMC11065116 DOI: 10.1093/function/zqae008] [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: 11/30/2023] [Revised: 02/19/2024] [Accepted: 02/19/2024] [Indexed: 05/07/2024] Open
Abstract
The Warburg Effect is a longstanding enigma in cancer biology. Despite the passage of 100 yr since its discovery, and the accumulation of a vast body of research on the subject, no convincing biochemical explanation has been given for the original observations of aerobic glycolysis in cancer cell metabolism. Here, we have worked out a first-principles quantitative analysis of the problem from the principles of stoichiometry and available electron balance. The results have been interpreted using Nath's unified theory of energy coupling and adenosine triphosphate (ATP) synthesis, and the original data of Warburg and colleagues have been analyzed from this new perspective. Use of the biomass yield based on ATP per unit substrate consumed, [Formula: see text], or the Nath-Warburg number, NaWa has been shown to excellently model the original data on the Warburg Effect with very small standard deviation values, and without employing additional fitted or adjustable parameters. Based on the results of the quantitative analysis, a novel conservative mechanism of synthesis, utilization, and recycling of ATP and other key metabolites (eg, lactate) is proposed. The mechanism offers fresh insights into metabolic symbiosis and coupling within and/or among proliferating cells. The fundamental understanding gained using our approach should help in catalyzing the development of more efficient metabolism-targeting anticancer drugs.
Collapse
Affiliation(s)
- Sunil Nath
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
- Institute of Molecular Psychiatry, Rheinische-Friedrichs-Wilhelm Universität Bonn, D‒53127 Bonn, Germany
| | - Rudi Balling
- Institute of Molecular Psychiatry, Rheinische-Friedrichs-Wilhelm Universität Bonn, D‒53127 Bonn, Germany
| |
Collapse
|
23
|
Soundararajan L, Warrier S, Dharmarajan A, Bhaskaran N. Predominant factors influencing reactive oxygen species in cancer stem cells. J Cell Biochem 2024; 125:3-21. [PMID: 37997702 DOI: 10.1002/jcb.30506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 10/17/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023]
Abstract
Reactive oxygen species (ROS) and its related signaling pathways and regulating molecules play a major role in the growth and development of cancer stem cells. The concept of ROS and cancer stem cells (CSCs) has been gaining much attention since the past decade and the evidence show that these CSCs possess robust self-renewal and tumorigenic potential and are resistant to conventional chemo- and radiotherapy and believed to be responsible for tumor progression, metastasis, and recurrence. It seems reasonable to say that cancer can be cured only if the CSCs are eradicated. ROS are Janus-faced molecules that can regulate cellular physiology as well as induce cytotoxicity, depending on the magnitude, duration, and site of generation. Unlike normal cancer cells, CSCs expel ROS efficiently by upregulating ROS scavengers. This unique redox regulation in CSCs protects them from ROS-mediated cell death and nullifies the effect of radiation, leading to chemoresistance and radioresistance. However, how these CSCs control ROS production by scavenging free radicals and how they maintain low levels of ROS is a challenging to understand and these attributes make CSCs as prime therapeutic targets. Here, we summarize the mechanisms of redox regulation in CSCs, with a focus on therapy resistance, its various pathways and microRNAs regulation, and the potential therapeutic implications of manipulating the ROS levels to eradicate CSCs. A better understanding of these molecules, their interactions in the CSCs may help us to adopt proper control and treatment measures.
Collapse
Affiliation(s)
- Loshini Soundararajan
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India
| | - Sudha Warrier
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Bangalore, Karnataka, India
- Cuor Stem Cellutions Pvt Ltd., Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Bangalore, Karnataka, India
- Department of Biotechnology, Sri Ramachandra Institute of Higher Education and Research, Faculty of Biomedical Sciences and Technology, Chennai, Tamil Nādu, India
| | - Arun Dharmarajan
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research (SRIHER), Faculty of Biomedical Sciences and Technology, Chennai, Tamil Nādu, India
- Stem Cell and Cancer Biology laboratory, Curtin University, Perth, Western Australia, Australia
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Western Australia, Australia
- Curtin Health and Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
- School of Human Sciences, University of Western Australia, Perth, Western Australia, Australia
| | - Natarajan Bhaskaran
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research (SRIHER), Faculty of Biomedical Sciences and Technology, Chennai, Tamil Nādu, India
| |
Collapse
|
24
|
Zhao Z, Xu X, Ma S, Li L. Expression and Prognostic Role of PANK1 in Glioma. Comb Chem High Throughput Screen 2024; 27:715-724. [PMID: 37138430 PMCID: PMC11092558 DOI: 10.2174/1386207326666230502103726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 02/25/2023] [Accepted: 03/06/2023] [Indexed: 05/05/2023]
Abstract
BACKGROUND Malignant gliomas are the most common type of primary malignant brain tumors. Pantothenate kinase 1 (PANK1) mRNA is highly expressed in several metabolic processes, implying that PANK1 plays a potential role in metabolic programming in cancers. However, the role of PANK1 in glioma has not been fully explored. METHODS Public datasets (The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Gravendeel and Rembrandt) and validation cohort were used to explore the expression of PANK1 in glioma tissues. Kaplan-Meier and Cox regression analyses were used to explore the relationship between PANK1 and prognosis in glioma. Cell proliferation and invasion were determined using Cell Counting Kit-8 (CCK8) and transwell invasion in vitro assays. RESULTS Analysis using the four public datasets and the validation cohort showed that PANK1 expression was significantly downregulated in glioma tissues compared with non-tumor tissues (P<0.01). PANK1 expression was negatively correlated with World Health Organization (WHO) grade, 1p/19q non-codeletion and isocitric dehydrogenase 1/2 (IDH1/2) wildtype. Furthermore, high expression of PANK1 was correlated with significantly better prognosis of glioma patients compared to patients with low expression of PANK1 (all P<0.01 in the four datasets). Besides, both lower-grade glioma (LGG) and glioblastoma multiform (GBM) patients with high expression of PANK1 had a significantly better prognosis than those with low expression of PANK1 in TCGA, Gravendeel and Rembrandt datasets (all P <0.01). Multivariate Cox regression analysis revealed that low PANK1 expression was an independent risk factor associated with a worse prognosis of glioma patients. Moreover, overexpression of PANK1 significantly inhibited the proliferation and invasion of U87 and U251 cells. CONCLUSION PANK1 expression is downregulated in glioma tissues and is a novel prognostic biomarker in glioma patients.
Collapse
Affiliation(s)
- Zhiming Zhao
- Department of Geriatrics, Renmin Hospital of Wuhan University, Wuchang District, Wuhan, 430060, China
| | - Xu Xu
- Department of Geriatrics, Renmin Hospital of Wuhan University, Wuchang District, Wuhan, 430060, China
| | - Shijing Ma
- Department of Geriatrics, Renmin Hospital of Wuhan University, Wuchang District, Wuhan, 430060, China
| | - Li Li
- Department of Geriatrics, Renmin Hospital of Wuhan University, Wuchang District, Wuhan, 430060, China
| |
Collapse
|
25
|
Szabo E, Nagy B, Czajlik A, Komlodi T, Ozohanics O, Tretter L, Ambrus A. Mitochondrial Alpha-Keto Acid Dehydrogenase Complexes: Recent Developments on Structure and Function in Health and Disease. Subcell Biochem 2024; 104:295-381. [PMID: 38963492 DOI: 10.1007/978-3-031-58843-3_13] [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] [Indexed: 07/05/2024]
Abstract
The present work delves into the enigmatic world of mitochondrial alpha-keto acid dehydrogenase complexes discussing their metabolic significance, enzymatic operation, moonlighting activities, and pathological relevance with links to underlying structural features. This ubiquitous family of related but diverse multienzyme complexes is involved in carbohydrate metabolism (pyruvate dehydrogenase complex), the citric acid cycle (α-ketoglutarate dehydrogenase complex), and amino acid catabolism (branched-chain α-keto acid dehydrogenase complex, α-ketoadipate dehydrogenase complex); the complexes all function at strategic points and also participate in regulation in these metabolic pathways. These systems are among the largest multienzyme complexes with at times more than 100 protein chains and weights ranging up to ~10 million Daltons. Our chapter offers a wealth of up-to-date information on these multienzyme complexes for a comprehensive understanding of their significance in health and disease.
Collapse
Affiliation(s)
- Eszter Szabo
- Department of Biochemistry, Semmelweis University, Budapest, Hungary
| | - Balint Nagy
- Department of Biochemistry, Semmelweis University, Budapest, Hungary
| | - Andras Czajlik
- Department of Biochemistry, Semmelweis University, Budapest, Hungary
| | - Timea Komlodi
- Department of Biochemistry, Semmelweis University, Budapest, Hungary
| | - Oliver Ozohanics
- Department of Biochemistry, Semmelweis University, Budapest, Hungary
| | - Laszlo Tretter
- Department of Biochemistry, Semmelweis University, Budapest, Hungary
| | - Attila Ambrus
- Department of Biochemistry, Semmelweis University, Budapest, Hungary.
| |
Collapse
|
26
|
Trejo-Solis C, Silva-Adaya D, Serrano-García N, Magaña-Maldonado R, Jimenez-Farfan D, Ferreira-Guerrero E, Cruz-Salgado A, Castillo-Rodriguez RA. Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma. Int J Mol Sci 2023; 24:17633. [PMID: 38139462 PMCID: PMC10744281 DOI: 10.3390/ijms242417633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/11/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023] Open
Abstract
Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose metabolism. Moreover, oncogenic signaling pathways induce the expression of metabolic genes, increasing the metabolic enzyme activities and thus the critical biosynthetic pathways to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates that are essential to accomplish the biosynthetic needs of glioma cells. In this review, we aim to explore how dysregulated metabolic enzymes and their metabolites from primary metabolism pathways in glioblastoma (GBM) such as glycolysis and glutaminolysis modulate anabolic and catabolic metabolic pathways as well as pro-oncogenic signaling and contribute to the formation, survival, growth, and malignancy of glioma cells. Also, we discuss promising therapeutic strategies by targeting the key players in metabolic regulation. Therefore, the knowledge of metabolic reprogramming is necessary to fully understand the biology of malignant gliomas to improve patient survival significantly.
Collapse
Affiliation(s)
- Cristina Trejo-Solis
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Laboratorio de Reprogramación Celular, Departamento de Neurofisiología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (D.S.-A.); (N.S.-G.); (R.M.-M.)
| | - Daniela Silva-Adaya
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Laboratorio de Reprogramación Celular, Departamento de Neurofisiología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (D.S.-A.); (N.S.-G.); (R.M.-M.)
| | - Norma Serrano-García
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Laboratorio de Reprogramación Celular, Departamento de Neurofisiología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (D.S.-A.); (N.S.-G.); (R.M.-M.)
| | - Roxana Magaña-Maldonado
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Laboratorio de Reprogramación Celular, Departamento de Neurofisiología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (D.S.-A.); (N.S.-G.); (R.M.-M.)
| | - Dolores Jimenez-Farfan
- Laboratorio de Inmunología, División de Estudios de Posgrado e Investigación, Facultad de Odontología, Universidad Nacional Autónoma de México, Ciudad de Mexico 04510, Mexico;
| | - Elizabeth Ferreira-Guerrero
- Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca 62100, Mexico; (E.F.-G.); (A.C.-S.)
| | - Arturo Cruz-Salgado
- Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca 62100, Mexico; (E.F.-G.); (A.C.-S.)
| | | |
Collapse
|
27
|
Zhang Y, Sun M, Zhao H, Wang Z, Shi Y, Dong J, Wang K, Wang X, Li X, Qi H, Zhao X. Neuroprotective Effects and Therapeutic Potential of Dichloroacetate: Targeting Metabolic Disorders in Nervous System Diseases. Int J Nanomedicine 2023; 18:7559-7581. [PMID: 38106446 PMCID: PMC10725694 DOI: 10.2147/ijn.s439728] [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: 09/15/2023] [Accepted: 11/28/2023] [Indexed: 12/19/2023] Open
Abstract
Dichloroacetate (DCA) is an investigational drug used to treat lactic acidosis and malignant tumours. It works by inhibiting pyruvate dehydrogenase kinase and increasing the rate of glucose oxidation. Some studies have documented the neuroprotective benefits of DCA. By reviewing these studies, this paper shows that DCA has multiple pharmacological activities, including regulating metabolism, ameliorating oxidative stress, attenuating neuroinflammation, inhibiting apoptosis, decreasing autophagy, protecting the blood‒brain barrier, improving the function of endothelial progenitor cells, improving mitochondrial dynamics, and decreasing amyloid β-protein. In addition, DCA inhibits the enzyme that metabolizes it, which leads to peripheral neurotoxicity due to drug accumulation that may be solved by individualized drug delivery and nanovesicle delivery. In summary, in this review, we analyse the mechanisms of neuroprotection by DCA in different diseases and discuss the causes of and solutions to its adverse effects.
Collapse
Affiliation(s)
- Yue Zhang
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Meiyan Sun
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Hongxiang Zhao
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Zhengyan Wang
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Yanan Shi
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Jianxin Dong
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Kaifang Wang
- Department of Anesthesia, Tangdu Hospital, Fourth Military Medical University, Xian, Shanxi Province, People’s Republic of China
| | - Xi Wang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Xingyue Li
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Haiyan Qi
- Department of Anesthesiology, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, People’s Republic of China
| | - Xiaoyong Zhao
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
- Department of Anesthesiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China
| |
Collapse
|
28
|
Liu Z, Villareal L, Goodla L, Kim H, Falcon DM, Haneef M, Martin DR, Zhang L, Lee HJ, Kremer D, Lyssiotis CA, Shah YM, Lin HC, Lin HK, Xue X. Iron promotes glycolysis to drive colon tumorigenesis. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166846. [PMID: 37579983 PMCID: PMC10530594 DOI: 10.1016/j.bbadis.2023.166846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 07/28/2023] [Accepted: 08/07/2023] [Indexed: 08/16/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer and is also the third leading cause of cancer-related death in the USA. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Macronutrients such as glucose are energy source for a cell. Many tumor cells exhibit increased aerobic glycolysis. Increased tissue micronutrient iron levels in both mice and humans are also associated with increased colon tumorigenesis. However, if iron drives colon carcinogenesis via affecting glucose metabolism is still not clear. Here we found the intracellular glucose levels in tumor colonoids were significantly increased after iron treatment. 13C-labeled glucose flux analysis indicated that the levels of several labeled glycolytic products were significantly increased, whereas several tricarboxylic acid cycle intermediates were significantly decreased in colonoids after iron treatment. Mechanistic studies showed that iron upregulated the expression of glucose transporter 1 (GLUT1) and mediated an inhibition of the pyruvate dehydrogenase (PDH) complex function via directly binding with tankyrase and/or pyruvate dehydrogenase kinase (PDHK) 3. Pharmacological inhibition of GLUT1 or PDHK reactivated PDH complex function and reduced high iron diet-enhanced tumor formation. In conclusion, excess iron promotes glycolysis and colon tumor growth at least partly through the inhibition of the PDH complex function.
Collapse
Affiliation(s)
- Zhaoli Liu
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Luke Villareal
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Lavanya Goodla
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Hyeoncheol Kim
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Daniel M Falcon
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Mohammad Haneef
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA
| | - David R Martin
- Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Li Zhang
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ho-Joon Lee
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Daniel Kremer
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Costas A Lyssiotis
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yatrik M Shah
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Henry C Lin
- Section of Gastroenterology, Medicine Service, New Mexico VA Health Care System, Albuquerque, NM 87108, USA; Division of Gastroenterology and Hepatology, Department of Medicine, the University of New Mexico, Albuquerque, NM, 87131, USA
| | - Hui-Kuan Lin
- Department of Pathology, Duke University, Durham, NC 27710, USA
| | - Xiang Xue
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA.
| |
Collapse
|
29
|
She W, Liu T, Li H, Wang Z, Guo Z, Liu Y, Liu Y. Reprogramming Energy Metabolism with Synthesized PDK Inhibitors Based on Dichloroacetate Derivatives and Targeted Delivery Systems for Enhanced Cancer Therapy. J Med Chem 2023; 66:14683-14699. [PMID: 37688544 DOI: 10.1021/acs.jmedchem.3c01197] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/11/2023]
Abstract
In many types of cancers, pyruvate dehydrogenase kinase (PDK) is abnormally overexpressed and has become a promising target for cancer therapy. However, few highly effective inhibitors of PDK have been reported to date. Herein, we designed and synthesized a series of PDK inhibitors based on dichloroacetate (DCA) and arsenicals. Of the 27 compounds, 1f demonstrated PDK inhibition with high efficiency at a cellular level (IC50 = 2.0 μM) and an enzyme level (EC50 = 68 nM), far more effective than that of DCA. In silico, in vitro, and in vivo studies demonstrated that 1f inhibited PDK, shifted the energy metabolism from aerobic glycolysis to oxidative phosphorylation, and induced cell apoptosis. Moreover, new 1f-loaded nanoparticles were developed, and the administration of high-drug-loading nanoparticles (0.15 mg/kg) caused up to 90% tumor shrinkage without any apparent toxicity. Hence, this study provided a novel metabolic therapy for cancer treatment.
Collapse
Affiliation(s)
- Wenyan She
- College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, P. R. China
| | - Tingting Liu
- State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry & School of Material Science and Engineering, Tiangong University, Tianjin 300387, P. R. China
| | - Haimei Li
- College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, P. R. China
| | - Zichen Wang
- College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, P. R. China
| | - Zhibin Guo
- State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry & School of Material Science and Engineering, Tiangong University, Tianjin 300387, P. R. China
| | - Yi Liu
- College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, P. R. China
- State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry & School of Material Science and Engineering, Tiangong University, Tianjin 300387, P. R. China
- School of Chemical and Environmental Engineering, Wuhan Polytechnic University, Wuhan 430023, P. R. China
- Hubei Key Laboratory of Radiation Chemistry and Functional Materials, Hubei University of Science and Technology, Xianning 437100, P. R. China
| | - Yujiao Liu
- State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry & School of Material Science and Engineering, Tiangong University, Tianjin 300387, P. R. China
| |
Collapse
|
30
|
Huang N, Chen Z, Yang X, Gao Y, Zhong J, Li Y, Xiao F, Wang X, Shi Y, Zhang N. Upstream open reading frame-encoded MP31 disrupts the mitochondrial quality control process and inhibits tumorigenesis in glioblastoma. Neuro Oncol 2023; 25:1947-1962. [PMID: 37280112 PMCID: PMC10628964 DOI: 10.1093/neuonc/noad099] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Indexed: 06/08/2023] Open
Abstract
BACKGROUND Mitochondrial hyperpolarization achieved by the elevation of mitochondrial quality control (MQC) activity is a hallmark of glioblastoma (GBM). Therefore, targeting the MQC process to disrupt mitochondrial homeostasis should be a promising approach for GBM therapy. METHODS We used 2-photon fluorescence microscopy, Fluorescence-Activated Cell Sorting, and confocal microscopy with specific fluorescent dyes to detect the mitochondrial membrane potential (MMP) and mitochondrial structures. Mitophagic flux was measured with mKeima. RESULTS MP31, a phosphatase and tensin homolog (PTEN) uORF-translated and mitochondria-localized micropeptide, disrupted the MQC process and inhibited GBM tumorigenesis. Re-expression of MP31 in patient-derived GBM cells induced MMP loss to trigger mitochondrial fission but blocked mitophagic flux, leading to the accumulation of damaged mitochondria in cells, followed by reactive oxygen species production and DNA damage. Mechanistically, MP31 inhibited lysosome function and blocked lysosome fusion with mitophagosomes by competing with V-ATPase A1 for lactate dehydrogenase B (LDHB) binding to induce lysosomal alkalinization. Furthermore, MP31 enhanced the sensitivity of GBM cells to TMZ by suppressing protective mitophay in vitro and in vivo, but showed no side effects on normal human astrocytes or microglia cells (MG). CONCLUSIONS MP31 disrupts cancerous mitochondrial homeostasis and sensitizes GBM cells to current chemotherapy, without inducing toxicity in normal human astrocytes and MG. MP31 is a promising candidate for GBM treatment.
Collapse
Affiliation(s)
- Nunu Huang
- Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, China
| | - Zhipeng Chen
- Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, China
| | - Xuesong Yang
- Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, China
| | - Yixin Gao
- Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, China
| | - Jian Zhong
- Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, China
| | - Yan Li
- Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, China
| | - Feizhe Xiao
- Department of Scientific Research Section, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiuxing Wang
- National Health Commission Key Laboratory of Antibody Techniques, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yu Shi
- Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology of the Ministry of Education of China Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Nu Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, China
| |
Collapse
|
31
|
Stacpoole PW. Clinical physiology and pharmacology of GSTZ1/MAAI. Biochem Pharmacol 2023; 217:115818. [PMID: 37742772 DOI: 10.1016/j.bcp.2023.115818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 09/05/2023] [Accepted: 09/21/2023] [Indexed: 09/26/2023]
Abstract
Herein I summarize the physiological chemistry and pharmacology of the bifunctional enzyme glutathione transferase zeta 1 (GSTZ1)/ maleylacetoacetate isomerase (MAAI) relevant to human physiology, drug metabolism and disease. MAAI is integral to the catabolism of the amino acids phenylalanine and tyrosine. Genetic or pharmacological inhibition of MAAI can be pathological in animals. However, to date, no clinical disease consequences are unequivocally attributable to inborn errors of this enzyme. MAAI is identical to the zeta 1 family isoform of GST, which biotransforms the investigational drug dichloroacetate (DCA) to the endogenous compound glyoxylate. DCA is a mechanism-based inhibitor of GSTZ1 that significantly reduces its rate of metabolism and increases accumulation of potentially harmful tyrosine intermediates and of the heme precursor δ-aminolevulinic acid (δ-ALA). GSTZ1 is most abundant in rodent and human liver, with its concentration several fold higher in cytoplasm than in mitochondria. Its activity and protein expression are dependent on the age of the host and the intracellular level of chloride ions. Gene association studies have linked GSTZ1 or its protein product to various physiological traits and pathologies. Haplotype variations in GSTZ1 influence the rate of DCA metabolism, enabling a genotyping strategy to allow potentially safe, precision-based drug dosing in clinical trials.
Collapse
Affiliation(s)
- Peter W Stacpoole
- Departments of Medicine and Biochemistry and Molecular Biology, University of Florida, College of Medicine, Gainesville, FL 32601, USA.
| |
Collapse
|
32
|
Dewdney B, Jenkins MR, Best SA, Freytag S, Prasad K, Holst J, Endersby R, Johns TG. From signalling pathways to targeted therapies: unravelling glioblastoma's secrets and harnessing two decades of progress. Signal Transduct Target Ther 2023; 8:400. [PMID: 37857607 PMCID: PMC10587102 DOI: 10.1038/s41392-023-01637-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/29/2023] [Accepted: 09/07/2023] [Indexed: 10/21/2023] Open
Abstract
Glioblastoma, a rare, and highly lethal form of brain cancer, poses significant challenges in terms of therapeutic resistance, and poor survival rates for both adult and paediatric patients alike. Despite advancements in brain cancer research driven by a technological revolution, translating our understanding of glioblastoma pathogenesis into improved clinical outcomes remains a critical unmet need. This review emphasises the intricate role of receptor tyrosine kinase signalling pathways, epigenetic mechanisms, and metabolic functions in glioblastoma tumourigenesis and therapeutic resistance. We also discuss the extensive efforts over the past two decades that have explored targeted therapies against these pathways. Emerging therapeutic approaches, such as antibody-toxin conjugates or CAR T cell therapies, offer potential by specifically targeting proteins on the glioblastoma cell surface. Combination strategies incorporating protein-targeted therapy and immune-based therapies demonstrate great promise for future clinical research. Moreover, gaining insights into the role of cell-of-origin in glioblastoma treatment response holds the potential to advance precision medicine approaches. Addressing these challenges is crucial to improving outcomes for glioblastoma patients and moving towards more effective precision therapies.
Collapse
Affiliation(s)
- Brittany Dewdney
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia.
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia.
| | - Misty R Jenkins
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
| | - Sarah A Best
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
| | - Saskia Freytag
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
| | - Krishneel Prasad
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
| | - Jeff Holst
- School of Biomedical Sciences, University of New South Wales, Sydney, 2052, Australia
| | - Raelene Endersby
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia
| | - Terrance G Johns
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia
| |
Collapse
|
33
|
Prabhu SS, Nair AS, Nirmala SV. Multifaceted roles of mitochondrial dysfunction in diseases: from powerhouses to saboteurs. Arch Pharm Res 2023; 46:723-743. [PMID: 37751031 DOI: 10.1007/s12272-023-01465-y] [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: 02/05/2023] [Accepted: 09/19/2023] [Indexed: 09/27/2023]
Abstract
The fact that mitochondria play a crucial part in energy generation has led to the nickname "powerhouses" of the cell being applied to them. They also play a significant role in many other cellular functions, including calcium signalling, apoptosis, and the creation of vital biomolecules. As a result, cellular function and health as a whole can be significantly impacted by mitochondrial malfunction. Indeed, malignancies frequently have increased levels of mitochondrial biogenesis and quality control. Adverse selection exists for harmful mitochondrial genome mutations, even though certain malignancies include modifications in the nuclear-encoded tricarboxylic acid cycle enzymes that generate carcinogenic metabolites. Since rare human cancers with mutated mitochondrial genomes are often benign, removing mitochondrial DNA reduces carcinogenesis. Therefore, targeting mitochondria offers therapeutic options since they serve several functions and are crucial to developing malignant tumors. Here, we discuss the various steps involved in the mechanism of cancer for which mitochondria plays a significant role, as well as the role of mitochondria in diseases other than cancer. It is crucial to understand mitochondrial malfunction to target these organelles for therapeutic reasons. This highlights the significance of investigating mitochondrial dysfunction in cancer and other disease research.
Collapse
Affiliation(s)
- Surapriya Surendranath Prabhu
- Department of Pharmaceutical Chemistry and Analysis, Amrita School of Pharmacy, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - Aathira Sujathan Nair
- Department of Pharmaceutical Chemistry and Analysis, Amrita School of Pharmacy, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - Saiprabha Vijayakumar Nirmala
- Department of Pharmaceutical Chemistry and Analysis, Amrita School of Pharmacy, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India.
| |
Collapse
|
34
|
Schoenmann N, Tannenbaum N, Hodgeman RM, Raju RP. Regulating mitochondrial metabolism by targeting pyruvate dehydrogenase with dichloroacetate, a metabolic messenger. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166769. [PMID: 37263447 PMCID: PMC10776176 DOI: 10.1016/j.bbadis.2023.166769] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/20/2023] [Accepted: 05/26/2023] [Indexed: 06/03/2023]
Abstract
Dichloroacetate (DCA) is a naturally occurring xenobiotic that has been used as an investigational drug for over 50 years. Originally found to lower blood glucose levels and alter fat metabolism in diabetic rats, this small molecule was found to serve primarily as a pyruvate dehydrogenase kinase inhibitor. Pyruvate dehydrogenase kinase inhibits pyruvate dehydrogenase complex, the catalyst for oxidative decarboxylation of pyruvate to produce acetyl coenzyme A. Several congenital and acquired disease states share a similar pathobiology with respect to glucose homeostasis under distress that leads to a preferential shift from the more efficient oxidative phosphorylation to glycolysis. By reversing this process, DCA can increase available energy and reduce lactic acidosis. The purpose of this review is to examine the literature surrounding this metabolic messenger as it presents exciting opportunities for future investigation and clinical application in therapy including cancer, metabolic disorders, cerebral ischemia, trauma, and sepsis.
Collapse
Affiliation(s)
- Nick Schoenmann
- Department of Emergency Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Nicholas Tannenbaum
- Department of Emergency Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Ryan M Hodgeman
- Department of Emergency Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Raghavan Pillai Raju
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States of America.
| |
Collapse
|
35
|
Denisova OV, Merisaari J, Huhtaniemi R, Qiao X, Yetukuri L, Jumppanen M, Kaur A, Pääkkönen M, von Schantz‐Fant С, Ohlmeyer M, Wennerberg K, Kauko O, Koch R, Aittokallio T, Taipale M, Westermarck J. PP2A-based triple-strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells. Mol Oncol 2023; 17:1803-1820. [PMID: 37458534 PMCID: PMC10483611 DOI: 10.1002/1878-0261.13488] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 05/08/2023] [Accepted: 07/13/2023] [Indexed: 07/27/2023] Open
Abstract
Mitochondrial glycolysis and hyperactivity of the phosphatidylinositol 3-kinase-protein kinase B (AKT) pathway are hallmarks of malignant brain tumors. However, kinase inhibitors targeting AKT (AKTi) or the glycolysis master regulator pyruvate dehydrogenase kinase (PDKi) have failed to provide clinical benefits for brain tumor patients. Here, we demonstrate that heterogeneous glioblastoma (GB) and medulloblastoma (MB) cell lines display only cytostatic responses to combined AKT and PDK targeting. Biochemically, the combined AKT and PDK inhibition resulted in the shutdown of both target pathways and priming to mitochondrial apoptosis but failed to induce apoptosis. In contrast, all tested brain tumor cell models were sensitive to a triplet therapy, in which AKT and PDK inhibition was combined with the pharmacological reactivation of protein phosphatase 2A (PP2A) by NZ-8-061 (also known as DT-061), DBK-1154, and DBK-1160. We also provide proof-of-principle evidence for in vivo efficacy in the intracranial GB and MB models by the brain-penetrant triplet therapy (AKTi + PDKi + PP2A reactivator). Mechanistically, PP2A reactivation converted the cytostatic AKTi + PDKi response to cytotoxic apoptosis, through PP2A-elicited shutdown of compensatory mitochondrial oxidative phosphorylation and by increased proton leakage. These results encourage the development of triple-strike strategies targeting mitochondrial metabolism to overcome therapy tolerance in brain tumors.
Collapse
Affiliation(s)
- Oxana V. Denisova
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | - Joni Merisaari
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
- Institute of BiomedicineUniversity of TurkuFinland
| | - Riikka Huhtaniemi
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | - Xi Qiao
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | - Laxman Yetukuri
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
- Institute for Molecular Medicine Finland (FIMM), HiLIFEUniversity of HelsinkiFinland
- Centre for Biostatistics and Epidemiology (OCBE)University of OsloNorway
| | - Mikael Jumppanen
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | - Amanpreet Kaur
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | - Mirva Pääkkönen
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | | | - Michael Ohlmeyer
- Icahn School of Medicine at Mount SinaiNew YorkNYUSA
- Atux Iskay LLCPlainsboroNJUSA
| | - Krister Wennerberg
- Institute for Molecular Medicine Finland (FIMM), HiLIFEUniversity of HelsinkiFinland
- Biotech Research & Innovation CentreUniversity of CopenhagenDenmark
| | - Otto Kauko
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | | | - Tero Aittokallio
- Institute for Molecular Medicine Finland (FIMM), HiLIFEUniversity of HelsinkiFinland
- Centre for Biostatistics and Epidemiology (OCBE)University of OsloNorway
- Institute for Cancer ResearchOslo University HospitalNorway
| | - Mikko Taipale
- Donnelly Centre for Cellular and Biomolecular ResearchUniversity of TorontoCanada
| | - Jukka Westermarck
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
- Institute of BiomedicineUniversity of TurkuFinland
| |
Collapse
|
36
|
Nogales JMS, Parras J, Zazo S. DDQN-based optimal targeted therapy with reversible inhibitors to combat the Warburg effect. Math Biosci 2023; 363:109044. [PMID: 37414271 DOI: 10.1016/j.mbs.2023.109044] [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: 02/25/2023] [Revised: 05/09/2023] [Accepted: 06/23/2023] [Indexed: 07/08/2023]
Abstract
We cover the Warburg effect with a three-component evolutionary model, where each component represents a different metabolic strategy. In this context, a scenario involving cells expressing three different phenotypes is presented. One tumour phenotype exhibits glycolytic metabolism through glucose uptake and lactate secretion. Lactate is used by a second malignant phenotype to proliferate. The third phenotype represents healthy cells, which performs oxidative phosphorylation. The purpose of this model is to gain a better understanding of the metabolic alterations associated with the Warburg effect. It is suitable to reproduce some of the clinical trials obtained in colorectal cancer and other even more aggressive tumours. It shows that lactate is an indicator of poor prognosis, since it favours the setting of polymorphic tumour equilibria that complicates its treatment. This model is also used to train a reinforcement learning algorithm, known as Double Deep Q-networks, in order to provide the first optimal targeted therapy based on experimental tumour growth inhibitors as genistein and AR-C155858. Our in silico solution includes the optimal therapy for all the tumour state space and also ensures the best possible quality of life for the patients, by considering the duration of treatment, the use of low-dose medications and the existence of possible contraindications. Optimal therapies obtained with Double Deep Q-networks are validated with the solutions of the Hamilton-Jacobi-Bellman equation.
Collapse
Affiliation(s)
- Jose M Sanz Nogales
- Information Processing and Telecommunications Center, Universidad Politécnica de Madrid, ETSI Telecomunicación, Av. Complutense 30, 28040 Madrid, Spain.
| | - Juan Parras
- Information Processing and Telecommunications Center, Universidad Politécnica de Madrid, ETSI Telecomunicación, Av. Complutense 30, 28040 Madrid, Spain
| | - Santiago Zazo
- Information Processing and Telecommunications Center, Universidad Politécnica de Madrid, ETSI Telecomunicación, Av. Complutense 30, 28040 Madrid, Spain
| |
Collapse
|
37
|
Martell E, Kuzmychova H, Senthil H, Kaul E, Chokshi CR, Venugopal C, Anderson CM, Singh SK, Sharif T. Compensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations. Acta Neuropathol Commun 2023; 11:110. [PMID: 37420311 PMCID: PMC10327182 DOI: 10.1186/s40478-023-01604-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 06/16/2023] [Indexed: 07/09/2023] Open
Abstract
Despite tremendous research efforts, successful targeting of aberrant tumor metabolism in clinical practice has remained elusive. Tumor heterogeneity and plasticity may play a role in the clinical failure of metabolism-targeting interventions for treating cancer patients. Moreover, compensatory growth-related processes and adaptive responses exhibited by heterogeneous tumor subpopulations to metabolic inhibitors are poorly understood. Here, by using clinically-relevant patient-derived glioblastoma (GBM) cell models, we explore the cross-talk between glycolysis, autophagy, and senescence in maintaining tumor stemness. We found that stem cell-like GBM tumor subpopulations possessed higher basal levels of glycolytic activity and increased expression of several glycolysis-related enzymes including, GLUT1/SLC2A1, PFKP, ALDOA, GAPDH, ENO1, PKM2, and LDH, compared to their non-stem-like counterparts. Importantly, bioinformatics analysis also revealed that the mRNA expression of glycolytic enzymes positively correlates with stemness markers (CD133/PROM1 and SOX2) in patient GBM tumors. While treatment with glycolysis inhibitors induced senescence in stem cell-like GBM tumor subpopulations, as evidenced by increased β-galactosidase staining and upregulation of the cell cycle regulators p21Waf1/Cip1/CDKN1A and p16INK4A/CDKN2A, these cells maintained their aggressive stemness features and failed to undergo apoptotic cell death. Using various techniques including autophagy flux and EGFP-MAP1LC3B+ puncta formation analysis, we determined that inhibition of glycolysis led to the induction of autophagy in stem cell-like GBM tumor subpopulations, but not in their non-stem-like counterparts. Similarly, blocking autophagy in stem cell-like GBM tumor subpopulations induced senescence-associated growth arrest without hampering stemness capacity or inducing apoptosis while reciprocally upregulating glycolytic activity. Combinatorial treatment of stem cell-like GBM tumor subpopulations with autophagy and glycolysis inhibitors blocked the induction of senescence while drastically impairing their stemness capacity which drove cells towards apoptotic cell death. These findings identify a novel and complex compensatory interplay between glycolysis, autophagy, and senescence that helps maintain stemness in heterogeneous GBM tumor subpopulations and provides a survival advantage during metabolic stress.
Collapse
Affiliation(s)
- Emma Martell
- Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Helgi Kuzmychova
- Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Harshal Senthil
- Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Esha Kaul
- Faculty of Science, University of Manitoba, Winnipeg, MB, Canada
| | - Chirayu R Chokshi
- Department of Biochemistry, McMaster University, Hamilton, ON, Canada
| | - Chitra Venugopal
- Department of Surgery, McMaster University, Hamilton, ON, Canada
| | - Christopher M Anderson
- Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Health Sciences Centre, Winnipeg, MB, Canada
| | - Sheila K Singh
- Department of Biochemistry, McMaster University, Hamilton, ON, Canada
- Department of Surgery, McMaster University, Hamilton, ON, Canada
| | - Tanveer Sharif
- Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
| |
Collapse
|
38
|
Wang J, Zhang Y, Luo Y, Liu ML, Niu W, Li ZC, Zhang B. PDK1 upregulates PINK1-mediated pulmonary endothelial cell mitophagy during hypoxia-induced pulmonary vascular remodeling. Mol Biol Rep 2023; 50:5585-5596. [PMID: 37162681 DOI: 10.1007/s11033-023-08428-y] [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: 12/20/2022] [Accepted: 04/04/2023] [Indexed: 05/11/2023]
Abstract
BACKGROUND Hypoxic pulmonary hypertension (HPH) is a complication of lung diseases with pulmonary vascular remodeling, although the underlying molecular mechanisms have not been fully elucidated. This study investigated the underlying molecular events by using a rat HPH model and primary pulmonary microvascular endothelial cells (PMVECs). METHODS AND RESULTS This study first established a rat HPH model and cultured PMVECs for transmission electron microscopic analysis and manipulation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) or phosphatase and tensin homolog-induced kinase 1 (PINK1) expression in vitro. After that, the cell viability was assessed and the expression of different proteins was assayed using cell viability and western blot assays, respectively. Reactive oxygen species production, apoptosis, NLR family pyrin domain containing 3 (NLRP3) expression, and the levels of interleukin (IL)-1β, IL-6, and IL-8 were also assessed, while the interaction of PDK1 and PINK1 was determined using co-immunoprecipitation/western blot assays. Hypoxia induced mitophagy in the PMVECs and upregulated PINK1/Parkin expression, whereas knockdown of PINK1 expression under hypoxic conditions inhibited cell proliferation but induced endothelial cell apoptosis in vitro, decreased reactive oxygen species production and NLRP3 expression, and reduced the levels of inflammatory factors in PMVECs. However, hypoxia induced PDK1 expression, whereas knockdown of PDK1 downregulated PINK1 expression. Furthermore, treatment of the model rats with the PDK1 inhibitor dichloroacetate (DCA) was able to decrease PINK1 expression. In addition, the PDK1 and PINK1 proteins could interact with each other in the mitochondria of PMVECs to regulate the cell viability. CONCLUSIONS This study revealed that PDK1 induced PMVEC proliferation but inhibited their apoptosis to participate in pulmonary vascular remodeling, ultimately leading to HPH through regulation of PINK1-mediated mitophagy signaling. Therefore, PINK1 is a novel therapeutic target for the control of HPH.
Collapse
Affiliation(s)
- Jing Wang
- School of Life Sciences, Northwest University, Xi'an, 710069, Shaanxi, China
| | - Yue Zhang
- School of Life Sciences, Northwest University, Xi'an, 710069, Shaanxi, China
| | - Ying Luo
- Department of Physiology and Pathophysiology, Air Force Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China
| | - Man Ling Liu
- Department of Physiology and Pathophysiology, Air Force Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China
| | - Wen Niu
- Department of Physiology and Pathophysiology, Air Force Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China
| | - Zhi Chao Li
- School of Life Sciences, Northwest University, Xi'an, 710069, Shaanxi, China.
- Department of Physiology and Pathophysiology, Air Force Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China.
| | - Bo Zhang
- Department of Physiology and Pathophysiology, Air Force Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China.
| |
Collapse
|
39
|
Casas-Benito A, Martínez-Herrero S, Martínez A. Succinate-Directed Approaches for Warburg Effect-Targeted Cancer Management, an Alternative to Current Treatments? Cancers (Basel) 2023; 15:2862. [PMID: 37345199 DOI: 10.3390/cancers15102862] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/22/2023] [Accepted: 05/08/2023] [Indexed: 06/23/2023] Open
Abstract
Approximately a century ago, Otto Warburg discovered that cancer cells use a fermentative rather than oxidative metabolism even though the former is more inefficient in terms of energy production per molecule of glucose. Cancer cells increase the use of this fermentative metabolism even in the presence of oxygen, and this process is called aerobic glycolysis or the Warburg effect. This alternative metabolism is mainly characterized by higher glycolytic rates, which allow cancer cells to obtain higher amounts of total ATP, and the production of lactate, but there are also an activation of protumoral signaling pathways and the generation of molecules that favor cancer progression. One of these molecules is succinate, a Krebs cycle intermediate whose concentration is increased in cancer and which is considered an oncometabolite. Several protumoral actions have been associated to succinate and its role in several cancer types has been already described. Despite playing a major role in metabolism and cancer, so far, the potential of succinate as a target in cancer prevention and treatment has remained mostly unexplored, as most previous Warburg-directed anticancer strategies have focused on other intermediates. In this review, we aim to summarize succinate's protumoral functions and discuss the use of succinate expression regulators as a potential cancer therapy strategy.
Collapse
Affiliation(s)
- Adrian Casas-Benito
- Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), 26006 Logroño, Spain
| | - Sonia Martínez-Herrero
- Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), 26006 Logroño, Spain
| | - Alfredo Martínez
- Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), 26006 Logroño, Spain
| |
Collapse
|
40
|
Burr AHP, Ji J, Ozler K, Mentrup HL, Eskiocak O, Yueh B, Cumberland R, Menk AV, Rittenhouse N, Marshall CW, Chiaranunt P, Zhang X, Mullinax L, Overacre-Delgoffe A, Cooper VS, Poholek AC, Delgoffe GM, Mollen KP, Beyaz S, Hand TW. Excess Dietary Sugar Alters Colonocyte Metabolism and Impairs the Proliferative Response to Damage. Cell Mol Gastroenterol Hepatol 2023; 16:287-316. [PMID: 37172822 PMCID: PMC10394273 DOI: 10.1016/j.jcmgh.2023.05.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 05/03/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023]
Abstract
BACKGROUND & AIMS The colonic epithelium requires continuous renewal by crypt resident intestinal stem cells (ISCs) and transit-amplifying (TA) cells to maintain barrier integrity, especially after inflammatory damage. The diet of high-income countries contains increasing amounts of sugar, such as sucrose. ISCs and TA cells are sensitive to dietary metabolites, but whether excess sugar affects their function directly is unknown. METHODS Here, we used a combination of 3-dimensional colonoids and a mouse model of colon damage/repair (dextran sodium sulfate colitis) to show the direct effect of sugar on the transcriptional, metabolic, and regenerative functions of crypt ISCs and TA cells. RESULTS We show that high-sugar conditions directly limit murine and human colonoid development, which is associated with a reduction in the expression of proliferative genes, adenosine triphosphate levels, and the accumulation of pyruvate. Treatment of colonoids with dichloroacetate, which forces pyruvate into the tricarboxylic acid cycle, restored their growth. In concert, dextran sodium sulfate treatment of mice fed a high-sugar diet led to massive irreparable damage that was independent of the colonic microbiota and its metabolites. Analyses on crypt cells from high-sucrose-fed mice showed a reduction in the expression of ISC genes, impeded proliferative potential, and increased glycolytic potential without a commensurate increase in aerobic respiration. CONCLUSIONS Taken together, our results indicate that short-term, excess dietary sucrose can directly modulate intestinal crypt cell metabolism and inhibit ISC/TA cell regenerative proliferation. This knowledge may inform diets that better support the treatment of acute intestinal injury.
Collapse
Affiliation(s)
- Ansen H P Burr
- Richard King Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Junyi Ji
- School of Medicine, Tsinghua University, Beijing, China
| | - Kadir Ozler
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | - Heather L Mentrup
- Department of Surgery, University of Pittsburgh School of Medicine. University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Onur Eskiocak
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | - Brian Yueh
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | - Rachel Cumberland
- Tumor Microenvironment Center, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Ashley V Menk
- Tumor Microenvironment Center, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Natalie Rittenhouse
- Richard King Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Chris W Marshall
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Pailin Chiaranunt
- Richard King Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Xiaoyi Zhang
- Richard King Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Gastroenterology, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center Children's Hospital
| | - Lauren Mullinax
- Richard King Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Gastroenterology, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center Children's Hospital
| | - Abigail Overacre-Delgoffe
- Richard King Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Vaughn S Cooper
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Amanda C Poholek
- Richard King Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Greg M Delgoffe
- Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania; Tumor Microenvironment Center, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Kevin P Mollen
- Department of Surgery, University of Pittsburgh School of Medicine. University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Semir Beyaz
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | - Timothy W Hand
- Richard King Mellon Institute for Pediatric Research, Pediatrics Department, Infectious Disease Section, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania.
| |
Collapse
|
41
|
Zhang R, Hao L, Chen P, Zhang G, Liu N. Multifunctional small-molecule theranostic agents for tumor-specific imaging and targeted chemotherapy. Bioorg Chem 2023; 137:106576. [PMID: 37182421 DOI: 10.1016/j.bioorg.2023.106576] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/17/2023] [Accepted: 04/26/2023] [Indexed: 05/16/2023]
Abstract
Cancer is one of the leading causes of death worldwide. Although great progress has been achieved in cancer diagnosis and treatment, novel therapies are still urgently needed to increase the efficacy and reduce the side effects of conventional therapies. Personalized medicine involves administering patients drugs that are specific to the characteristics of their tumors, and has significantly reduced side effects and increased overall survival rates. Multifunctional theranostic drugs are designed to combine diagnostic and therapeutic functions into a single molecule, which reduces the number of drugs administered to patients and increases patient compliance, and have shown great potential in propelling personalized medicine. This review focuses on multifunctional small-molecule theranostic agents for tumor-specific imaging and targeted chemotherapy, with a particular emphasis placed on highlighting design strategies and application in vitro or in vivo. The challenges and future perspectives of multifunctional small molecules are also discussed.
Collapse
Affiliation(s)
- Renshuai Zhang
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China
| | - Li Hao
- Department of Gerontology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 528051, China
| | - Pengwei Chen
- Hainan Key Laboratory for ReseCarch and Development of Natural Products from Li Folk Medicine, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China.
| | - Gang Zhang
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China.
| | - Ning Liu
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China.
| |
Collapse
|
42
|
Warrier NM, Kelkar N, Johnson CT, Govindarajan T, Prabhu V, Kumar P. Understanding cancer stem cells and plasticity: Towards better therapeutics. Eur J Cell Biol 2023; 102:151321. [PMID: 37137199 DOI: 10.1016/j.ejcb.2023.151321] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 04/27/2023] [Accepted: 04/28/2023] [Indexed: 05/05/2023] Open
Abstract
The ability of cancer cells to finally overcome various lines of treatment in due course has always baffled the scientific community. Even with the most promising therapies, relapse is ultimately seen, and this resilience has proved to be a major hurdle in the management of cancer. Accumulating evidence now attributes this resilience to plasticity. Plasticity is the ability of cells to change their properties and is substantial as it helps in normal tissue regeneration or post-injury repair processes. It also helps in the overall maintenance of homeostasis. Unfortunately, this critical ability of cells, when activated incorrectly, can lead to numerous diseases, including cancer. Therefore, in this review, we focus on the plasticity aspect with an emphasis on cancer stem cells (CSCs). We discuss the various forms of plasticity that provide survival advantages to CSCs. Moreover, we explore various factors that affect plasticity. Furthermore, we provide the therapeutic implications of plasticity. Finally, we provide an insight into the future targeted therapies involving plasticity for better clinical outcomes.
Collapse
Affiliation(s)
- Neerada Meenakshi Warrier
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Nachiket Kelkar
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Carol Tresa Johnson
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | | | - Vijendra Prabhu
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
| | - Praveen Kumar
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
| |
Collapse
|
43
|
Wawrzkiewicz-Jałowiecka A, Lalik A, Lukasiak A, Richter-Laskowska M, Trybek P, Ejfler M, Opałka M, Wardejn S, Delfino DV. Potassium Channels, Glucose Metabolism and Glycosylation in Cancer Cells. Int J Mol Sci 2023; 24:ijms24097942. [PMID: 37175655 PMCID: PMC10178682 DOI: 10.3390/ijms24097942] [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: 03/29/2023] [Revised: 04/24/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Potassium channels emerge as one of the crucial groups of proteins that shape the biology of cancer cells. Their involvement in processes like cell growth, migration, or electric signaling, seems obvious. However, the relationship between the function of K+ channels, glucose metabolism, and cancer glycome appears much more intriguing. Among the typical hallmarks of cancer, one can mention the switch to aerobic glycolysis as the most favorable mechanism for glucose metabolism and glycome alterations. This review outlines the interconnections between the expression and activity of potassium channels, carbohydrate metabolism, and altered glycosylation in cancer cells, which have not been broadly discussed in the literature hitherto. Moreover, we propose the potential mediators for the described relations (e.g., enzymes, microRNAs) and the novel promising directions (e.g., glycans-orinented drugs) for further research.
Collapse
Affiliation(s)
- Agata Wawrzkiewicz-Jałowiecka
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Anna Lalik
- Department of Systems Biology and Engineering, Silesian University of Technology, 44-100 Gliwice, Poland
- Biotechnology Center, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Agnieszka Lukasiak
- Department of Physics and Biophysics, Institute of Biology, Warsaw University of Life Sciences, 02-776 Warsaw, Poland
| | - Monika Richter-Laskowska
- The Centre for Biomedical Engineering, Łukasiewicz Research Network-Krakow Institute of Technology, 30-418 Krakow, Poland
| | - Paulina Trybek
- Institute of Physics, University of Silesia in Katowice, 41-500 Chorzów, Poland
| | - Maciej Ejfler
- Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Maciej Opałka
- Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Sonia Wardejn
- Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Domenico V Delfino
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy
| |
Collapse
|
44
|
Park JW. Metabolic Rewiring in Adult-Type Diffuse Gliomas. Int J Mol Sci 2023; 24:ijms24087348. [PMID: 37108511 PMCID: PMC10138713 DOI: 10.3390/ijms24087348] [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: 03/15/2023] [Revised: 04/10/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Multiple metabolic pathways are utilized to maintain cellular homeostasis. Given the evidence that altered cell metabolism significantly contributes to glioma biology, the current research efforts aim to improve our understanding of metabolic rewiring between glioma's complex genotype and tissue context. In addition, extensive molecular profiling has revealed activated oncogenes and inactivated tumor suppressors that directly or indirectly impact the cellular metabolism that is associated with the pathogenesis of gliomas. The mutation status of isocitrate dehydrogenases (IDHs) is one of the most important prognostic factors in adult-type diffuse gliomas. This review presents an overview of the metabolic alterations in IDH-mutant gliomas and IDH-wildtype glioblastoma (GBM). A particular focus is placed on targeting metabolic vulnerabilities to identify new therapeutic strategies for glioma.
Collapse
Affiliation(s)
- Jong-Whi Park
- Department of Life Sciences, College of BioNano Technology, Gachon University, Seongnam 13120, Republic of Korea
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea
- Neuroscience Research Institute, Gachon University, Incheon 21565, Republic of Korea
| |
Collapse
|
45
|
Niu N, Ye J, Hu Z, Zhang J, Wang Y. Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis. Int J Mol Sci 2023; 24:ijms24087076. [PMID: 37108242 PMCID: PMC10139088 DOI: 10.3390/ijms24087076] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/23/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
One important feature of tumour development is the regulatory role of metabolic plasticity in maintaining the balance of mitochondrial oxidative phosphorylation and glycolysis in cancer cells. In recent years, the transition and/or function of metabolic phenotypes between mitochondrial oxidative phosphorylation and glycolysis in tumour cells have been extensively studied. In this review, we aimed to elucidate the characteristics of metabolic plasticity (emphasizing their effects, such as immune escape, angiogenesis migration, invasiveness, heterogeneity, adhesion, and phenotypic properties of cancers, among others) on tumour progression, including the initiation and progression phases. Thus, this article provides an overall understanding of the influence of abnormal metabolic remodeling on malignant proliferation and pathophysiological changes in carcinoma.
Collapse
Affiliation(s)
- Nan Niu
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
- College of Physics and Optoelectronic Engineering, Canghai Campus of Shenzhen University, Shenzhen 518060, China
| | - Jinfeng Ye
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
| | - Zhangli Hu
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
| | - Junbin Zhang
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
| | - Yun Wang
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
| |
Collapse
|
46
|
Lu B, Nie XH, Yin R, Ding P, Su ZZ, Qiu S, Qian YF. PGAM4 silencing inhibited glycolysis and chemoresistance to temozolomide in glioma cells. Cell Biol Int 2023; 47:776-786. [PMID: 36576012 DOI: 10.1002/cbin.11983] [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: 06/02/2022] [Revised: 12/12/2022] [Accepted: 12/17/2022] [Indexed: 12/29/2022]
Abstract
Gliomas account for about 80% of malignant brain tumors. The incidence of a new brain tumor is 6.4 per 100,000 persons per year with an overall 5-year survival rate of 33.4%. Regardless of the great advances that have been made in recent years, the causes and pathogenesis of glioma remain unclear. Here we study how phosphoglycerate mutase 4 (PGAM4) contributes to glioma. Using a variety of methods to examine glioma cell viability, proliferation, apoptosis, glycolysis, as well as ChIP coanalysis with modified histone H3, we showed that PGAM4 was significantly upregulated in patients with glioma and associated with poor survival. Silencing PGAM4 attenuated cell viability, proliferation, and glycolysis in T98G cells and suppressed tumor growth in vivo, while overexpressing PGAM4 promoted cell viability, proliferation, and glycolysis in U251 cells via regulating glycolysis pathway. Study also revealed that PGAM4 was regulated by EP300-mediated modifications of H3K27ac. PGAM4 silencing inhibited cell viability and proliferation, suppressed tumor growth, and decreased chemoresistance to temozolomide in glioma cells through suppressing glycolysis.
Collapse
Affiliation(s)
- Bin Lu
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
| | - Xiao-Hu Nie
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
| | - Rui Yin
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
| | - Peng Ding
- Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhong-Zhou Su
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
| | - Sheng Qiu
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
| | - Ya-Fang Qian
- Department of orthopedics, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, China
| |
Collapse
|
47
|
Cruz N, Herculano-Carvalho M, Roque D, Faria CC, Cascão R, Ferreira HA, Reis CP, Matela N. Highlighted Advances in Therapies for Difficult-To-Treat Brain Tumours Such as Glioblastoma. Pharmaceutics 2023; 15:pharmaceutics15030928. [PMID: 36986790 PMCID: PMC10054750 DOI: 10.3390/pharmaceutics15030928] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/25/2023] [Accepted: 03/10/2023] [Indexed: 03/15/2023] Open
Abstract
Glioblastoma multiforme (GBM) remains a challenging disease, as it is the most common and deadly brain tumour in adults and has no curative solution and an overall short survival time. This incurability and short survival time means that, despite its rarity (average incidence of 3.2 per 100,000 persons), there has been an increased effort to try to treat this disease. Standard of care in newly diagnosed glioblastoma is maximal tumour resection followed by initial concomitant radiotherapy and temozolomide (TMZ) and then further chemotherapy with TMZ. Imaging techniques are key not only to diagnose the extent of the affected tissue but also for surgery planning and even for intraoperative use. Eligible patients may combine TMZ with tumour treating fields (TTF) therapy, which delivers low-intensity and intermediate-frequency electric fields to arrest tumour growth. Nonetheless, the blood–brain barrier (BBB) and systemic side effects are obstacles to successful chemotherapy in GBM; thus, more targeted, custom therapies such as immunotherapy and nanotechnological drug delivery systems have been undergoing research with varying degrees of success. This review proposes an overview of the pathophysiology, possible treatments, and the most (not all) representative examples of the latest advancements.
Collapse
Affiliation(s)
- Nuno Cruz
- Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- iMED.ULisboa, Research Institute for Medicines, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
| | - Manuel Herculano-Carvalho
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
- Department of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte (CHULN), 1649-028 Lisboa, Portugal
| | - Diogo Roque
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
- Department of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte (CHULN), 1649-028 Lisboa, Portugal
| | - Cláudia C. Faria
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
- Department of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte (CHULN), 1649-028 Lisboa, Portugal
| | - Rita Cascão
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Hugo Alexandre Ferreira
- Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
| | - Catarina Pinto Reis
- Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- iMED.ULisboa, Research Institute for Medicines, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
- Correspondence: (C.P.R.); (N.M.); Tel.: +351-217-946-400 (ext. 14244) (C.P.R.); Fax: +351-217-946-470 (C.P.R.)
| | - Nuno Matela
- Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Correspondence: (C.P.R.); (N.M.); Tel.: +351-217-946-400 (ext. 14244) (C.P.R.); Fax: +351-217-946-470 (C.P.R.)
| |
Collapse
|
48
|
Stacpoole PW, McCall CE. The pyruvate dehydrogenase complex: Life's essential, vulnerable and druggable energy homeostat. Mitochondrion 2023; 70:59-102. [PMID: 36863425 DOI: 10.1016/j.mito.2023.02.007] [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: 08/02/2022] [Revised: 01/30/2023] [Accepted: 02/13/2023] [Indexed: 03/04/2023]
Abstract
Found in all organisms, pyruvate dehydrogenase complexes (PDC) are the keystones of prokaryotic and eukaryotic energy metabolism. In eukaryotic organisms these multi-component megacomplexes provide a crucial mechanistic link between cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle. As a consequence, PDCs also influence the metabolism of branched chain amino acids, lipids and, ultimately, oxidative phosphorylation (OXPHOS). PDC activity is an essential determinant of the metabolic and bioenergetic flexibility of metazoan organisms in adapting to changes in development, nutrient availability and various stresses that challenge maintenance of homeostasis. This canonical role of the PDC has been extensively probed over the past decades by multidisciplinary investigations into its causal association with diverse physiological and pathological conditions, the latter making the PDC an increasingly viable therapeutic target. Here we review the biology of the remarkable PDC and its emerging importance in the pathobiology and treatment of diverse congenital and acquired disorders of metabolic integration.
Collapse
Affiliation(s)
- Peter W Stacpoole
- Department of Medicine (Division of Endocrinology, Metabolism and Diabetes), and Department of Biochemistry and Molecular Biology, University of Florida, College of Medicine, Gainesville, FL, United States.
| | - Charles E McCall
- Department of Internal Medicine and Translational Sciences, and Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| |
Collapse
|
49
|
Fu X, Kimura Y, Toku Y, Song G, Ju Y. Stiffer-Matrix-Induced PGC-1α Upregulation Enhanced Mitochondrial Biogenesis and Oxidative Stress Resistance in Non-small Cell Lung Cancer. Cell Mol Bioeng 2023; 16:69-80. [PMID: 36660585 PMCID: PMC9842820 DOI: 10.1007/s12195-022-00751-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: 10/03/2022] [Accepted: 11/22/2022] [Indexed: 12/04/2022] Open
Abstract
Introduction Metabolic strategies in different microenvironments can affect cancer metabolic adaptation, ultimately influencing the therapeutic response. Understanding the metabolic alterations of cancer cells in different microenvironments is critical for therapeutic success. Methods In this study, we cultured non-small cell lung cancer cells in three different microenvironments (two-dimensional (2D) plates, soft elastic three-dimensional (3D) porous 2 wt% scaffolds, and stiff elastic 3D porous 4 wt% scaffolds) to investigate the effects of different matrix elasticity as well as 2D and 3D culture settings on the metabolic adaptation of cancer cells. Results The results revealed that PGC-1α expression is sensitive to the elasticity of the 3D scaffold. PGC-1α expression was markedly increased in cancer cells cultured in stiff elastic 3D porous 4 wt% scaffolds compared with cells cultured in soft elastic 3D porous 2 wt% scaffolds or 2D plates, enhancing mitochondrial biogenesis and oxidative stress resistance of non-small cell lung cancer through increased reactive oxygen species (ROS) detoxification capacity. However, phosphofructokinase-1 (PFK-1) expression, a key rate-limiting enzyme in glycolysis, did not change significantly in the three microenvironments, indicating that microenvironments may not affect the early stage of glycolysis. Conversely, monocarboxylate transporter 1 (MCT1) expression in 3D culture was significantly reduced compared to 2D culture but without significant difference between soft and stiff scaffolds, indicating that MCT1 expression is more sensitive to the shape of the different cultures of 2D and 3D microenvironment surrounding cells but is unaffected by the scaffold elasticity. Conclusions Together, these results demonstrate that differences in the microenvironment of cancer cells profoundly impact their metabolic response.
Collapse
Affiliation(s)
- Xiaorong Fu
- Department of Micro-Nano Mechanical Science and Engineering, Graduate School of Engineering, Nagoya University, Nagoya City, Aichi State Japan
| | - Yasuhiro Kimura
- Department of Micro-Nano Mechanical Science and Engineering, Graduate School of Engineering, Nagoya University, Nagoya City, Aichi State Japan
| | - Yuhki Toku
- Department of Micro-Nano Mechanical Science and Engineering, Graduate School of Engineering, Nagoya University, Nagoya City, Aichi State Japan
| | - Guanbin Song
- College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing, 400030 People’s Republic of China
| | - Yang Ju
- Department of Micro-Nano Mechanical Science and Engineering, Graduate School of Engineering, Nagoya University, Nagoya City, Aichi State Japan
| |
Collapse
|
50
|
Pal S, Sharma A, Mathew SP, Jaganathan BG. Targeting cancer-specific metabolic pathways for developing novel cancer therapeutics. Front Immunol 2022; 13:955476. [PMID: 36618350 PMCID: PMC9815821 DOI: 10.3389/fimmu.2022.955476] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 10/20/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer is a heterogeneous disease characterized by various genetic and phenotypic aberrations. Cancer cells undergo genetic modifications that promote their proliferation, survival, and dissemination as the disease progresses. The unabated proliferation of cancer cells incurs an enormous energy demand that is supplied by metabolic reprogramming. Cancer cells undergo metabolic alterations to provide for increased energy and metabolite requirement; these alterations also help drive the tumor progression. Dysregulation in glucose uptake and increased lactate production via "aerobic glycolysis" were described more than 100 years ago, and since then, the metabolic signature of various cancers has been extensively studied. However, the extensive research in this field has failed to translate into significant therapeutic intervention, except for treating childhood-ALL with amino acid metabolism inhibitor L-asparaginase. Despite the growing understanding of novel metabolic alterations in tumors, the therapeutic targeting of these tumor-specific dysregulations has largely been ineffective in clinical trials. This chapter discusses the major pathways involved in the metabolism of glucose, amino acids, and lipids and highlights the inter-twined nature of metabolic aberrations that promote tumorigenesis in different types of cancer. Finally, we summarise the therapeutic interventions which can be used as a combinational therapy to target metabolic dysregulations that are unique or common in blood, breast, colorectal, lung, and prostate cancer.
Collapse
Affiliation(s)
- Soumik Pal
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Amit Sharma
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Sam Padalumavunkal Mathew
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Bithiah Grace Jaganathan
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India,Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati, Assam, India,*Correspondence: Bithiah Grace Jaganathan,
| |
Collapse
|