Multiple metabolic pathways fuel the truncated tricarboxylic acid cycle of the prostate to sustain constant citrate production and secretion

Frégeau-Proulx, Lilianne; Lacouture, Aurélie; Berthiaume, Line; Weidmann, Cindy; Harvey, Mario; Gonthier, Kevin; Pelletier, J.M.; Neveu, Bertrand; Jobin, Cynthia; Bastien, Dominic; Bergeron, Alain; Fradet, Yves; Lacombe, Louis; Laverdière, Isabelle; Atallah, Chantal; Pouliot, Frédéric; Audet-Walsh, Étienne

doi:10.1016/j.molmet.2022.101516

Cited by 25 publications

(25 citation statements)

References 42 publications

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“…Altered glucose metabolism is unique in the PCa context because, as discussed above, normal prostate epithelium has a distinct baseline metabolic profile. Due to the tissue-specific truncation of the TCA cycle for citrate production, the metabolic alteration that signals prostate carcinogenesis is, paradoxically, a reversion to “normal” glucose metabolism (transition from energy inefficient glycolytic metabolism to energy efficient oxidative metabolism) [ 108 ]. Nevertheless, elevated glucose consumption and lactic acid secretion remains a relevant metabolic alteration as the disease progresses towards more treatment-resistant and aggressive phenotypes [ 50 ].…”

Section: Major Bioenergetic Sourcesmentioning

confidence: 99%

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

et al. 2022

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There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to understand the relationship between distinctive metabolic features, androgen receptor signaling, genetic drivers in prostate cancer, and the tumor microenvironment (symbiotic and competitive metabolic interactions) to identify metabolic vulnerabilities. We explore the links between metabolism and gene regulation, and thus the unique metabolic signatures that define the malignant phenotypes at given stages of prostate tumor progression. We also provide an overview of current metabolism-based pharmacological strategies to be developed or repurposed for metabolism-based therapeutics for castration-resistant prostate cancer.

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Section: Major Bioenergetic Sourcesmentioning

confidence: 99%

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

et al. 2022

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“…Here, we describe an isolation and purification protocol of prostate epithelial cells to grow organoids ex vivo , adapted from the protocol by Lacouture et al. [14] for purification of mammary epithelial cells and recently used to study the unique metabolic program of the prostate [15] . This protocol is simple and thus does not require FACS, facilitating its implementation in most research laboratories.…”

Section: Description Of Protocolmentioning

confidence: 99%

“… Note that CD49f is a plasma membrane marker highly expressed by basal epithelial cells, which are the most potent cells to generate prostate organoids ex vivo [3] . Note that CD49f is also expressed at intermediate levels by luminal epithelial cells, as shown by flow cytometry [ 3 , 4 , 7 , 15 ]. Cell sorting using flow cytometry allows purification of individual cell types, but we found that magnetic-based purification enriches for both epithelial cell types [15] .…”

Section: Description Of Protocolmentioning

confidence: 99%

“…Note that CD49f is also expressed at intermediate levels by luminal epithelial cells, as shown by flow cytometry [ 3 , 4 , 7 , 15 ]. Cell sorting using flow cytometry allows purification of individual cell types, but we found that magnetic-based purification enriches for both epithelial cell types [15] . The current protocol thus allows generation of prostate organoids from a combination of basal and luminal epithelial cells.…”

Section: Description Of Protocolmentioning

confidence: 99%

“…1 F), consistent with the presence of luminal (secretory) epithelial cells in these organoids. In the article by Frégeau-Proulx et al., mouse prostate organoids were used to study the unique citrate-secretory phenotype of the prostate ex vivo with gas chromatography – mass spectrometry (GC-MS) metabolomics [15] . These organoids were shown to recapitulate the glandular structure of the prostate, with the presence of internal lumen for secretion, as well as to produce and secrete citrate, as the prostate gland does in vivo .…”

Section: Description Of Protocolmentioning

confidence: 99%

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FACS-Free isolation and purification protocol of mouse prostate epithelial cells for organoid primary culture

Frégeau-Proulx

Lacouture²,

Weidmann³

et al. 2022

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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

et al. 2023

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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.

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Multiple metabolic pathways fuel the truncated tricarboxylic acid cycle of the prostate to sustain constant citrate production and secretion

Cited by 25 publications

References 42 publications

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

FACS-Free isolation and purification protocol of mouse prostate epithelial cells for organoid primary culture

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

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