Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic-mitochondrial tricarboxylic acid cycle that can be targeted for therapeutic purposes in prostate cancer.

Autor:	Gonthier K; Endocrinology - Nephrology Research Axis, CHU de Québec-Université Laval Research Center, Canada.; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Canada.; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada., Weidmann C; Endocrinology - Nephrology Research Axis, CHU de Québec-Université Laval Research Center, Canada.; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada., Berthiaume L; Endocrinology - Nephrology Research Axis, CHU de Québec-Université Laval Research Center, Canada.; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada., Jobin C; Endocrinology - Nephrology Research Axis, CHU de Québec-Université Laval Research Center, Canada.; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Canada.; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada., Lacouture A; Endocrinology - Nephrology Research Axis, CHU de Québec-Université Laval Research Center, Canada.; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Canada.; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada., Lafront C; Endocrinology - Nephrology Research Axis, CHU de Québec-Université Laval Research Center, Canada.; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Canada.; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada., Harvey M; Endocrinology - Nephrology Research Axis, CHU de Québec-Université Laval Research Center, Canada.; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada., Neveu B; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.; Oncology Axis, Centre de recherche du CHU de Québec - Université Laval, Canada., Loehr J; Endocrinology - Nephrology Research Axis, CHU de Québec-Université Laval Research Center, Canada.; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada., Bergeron A; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.; Oncology Axis, Centre de recherche du CHU de Québec - Université Laval, Canada.; Department of Surgery, Faculty of Medicine, Université Laval, Québec, Canada., Fradet Y; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.; Oncology Axis, Centre de recherche du CHU de Québec - Université Laval, Canada.; Department of Surgery, Faculty of Medicine, Université Laval, Québec, Canada., Lacombe L; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.; Oncology Axis, Centre de recherche du CHU de Québec - Université Laval, Canada.; Department of Surgery, Faculty of Medicine, Université Laval, Québec, Canada., Riopel J; Anatomopathology Service, Department of Laboratory Medicine, CHU de Québec - Université Laval, Canada., Latulippe É; Department of Pathology, CHU de Québec - Université Laval, Canada., Atallah C; Department of Pathology, CHU de Québec - Université Laval, Canada., Shum M; Endocrinology - Nephrology Research Axis, CHU de Québec-Université Laval Research Center, Canada.; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Canada., Lambert JP; Endocrinology - Nephrology Research Axis, CHU de Québec-Université Laval Research Center, Canada.; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Canada.; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.; Big Data Research Center, Université Laval, Québec, QC, Canada., Pouliot F; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.; Oncology Axis, Centre de recherche du CHU de Québec - Université Laval, Canada.; Department of Surgery, Faculty of Medicine, Université Laval, Québec, Canada., Pelletier M; Infectious and Immune Disease Axis, CHU de Québec-Université Laval Research Center, Canada.; ARThrite Research Center, Université Laval, Québec, QC, Canada.; Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Québec, QC, Canada., Audet-Walsh É; Endocrinology - Nephrology Research Axis, CHU de Québec-Université Laval Research Center, Canada.; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Canada.; Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.
Jazyk:	angličtina
Zdroj:	Molecular oncology [Mol Oncol] 2023 Oct; Vol. 17 (10), pp. 2109-2125. Date of Electronic Publication: 2023 Jul 19.
DOI:	10.1002/1878-0261.13441
Abstrakt:	The androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1), but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa. Mouse models, in vitro human PCa cell lines, and human patient-derived organoids (PDOs) were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analyses and gas chromatography-mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo. In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and PDOs. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry-based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo. These results demonstrate that PCa cells have a hybrid cytoplasmic-mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target. (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze:	MEDLINE
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