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

Authors :
Kevin Gonthier
Cindy Weidmann
Line Berthiaume
Cynthia Jobin
Aurélie Lacouture
Camille Lafront
Mario Harvey
Bertrand Neveu
Jérémy Loehr
Alain Bergeron
Yves Fradet
Louis Lacombe
Julie Riopel
Éva Latulippe
Chantal Atallah
Michael Shum
Jean‐Philippe Lambert
Frédéric Pouliot
Martin Pelletier
Étienne Audet‐Walsh
Source :
Molecular Oncology, Vol 17, Iss 10, Pp 2109-2125 (2023)
Publication Year :
2023
Publisher :
Wiley, 2023.

Abstract

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.

Details

Language :
English
ISSN :
18780261 and 15747891
Volume :
17
Issue :
10
Database :
Directory of Open Access Journals
Journal :
Molecular Oncology
Publication Type :
Academic Journal
Accession number :
edsdoj.b60b3bf0f71f4ae9996565ed221a4aac
Document Type :
article
Full Text :
https://doi.org/10.1002/1878-0261.13441