Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer

David A. Bader, Sean M. Hartig, Vasanta Putluri, Christopher Foley, Mark P. Hamilton, Eric A. Smith, Pradip K. Saha, Anil Panigrahi, Christopher Walker, Lin Zong, Heidi Martini-Stoica, Rui Chen, Kimal Rajapakshe, Cristian Coarfa, Arun Sreekumar, Nicholas Mitsiades, James A. Bankson, Michael M. Ittmann, Bert W. O’Malley, Nagireddy PutluriSean E. McGuire

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Specific metabolic underpinnings of androgen receptor (AR)-driven growth in prostate adenocarcinoma (PCa) are largely undefined, hindering the development of strategies to leverage the metabolic dependencies of this disease when hormonal manipulations fail. Here we show that the mitochondrial pyruvate carrier (MPC), a critical metabolic conduit linking cytosolic and mitochondrial metabolism, is transcriptionally regulated by AR. Experimental MPC inhibition restricts proliferation and metabolic outputs of the citric acid cycle (TCA) including lipogenesis and oxidative phosphorylation in AR-driven PCa models. Mechanistically, metabolic disruption resulting from MPC inhibition activates the eIF2α/ATF4 integrated stress response (ISR). ISR signalling prevents cell cycle progression while coordinating salvage efforts, chiefly enhancing glutamine assimilation into the TCA, to regain metabolic homeostasis. We confirm that MPC function is operant in PCa tumours in vivo using isotopomeric metabolic flux analysis. In turn, we apply a clinically viable small molecule targeting the MPC, MSDC0160, to pre-clinical PCa models and find that MPC inhibition suppresses tumour growth in hormone-responsive and castrate-resistant conditions. Collectively, our findings characterize the MPC as a tractable therapeutic target in AR-driven prostate tumours.

Original languageEnglish (US)
Pages (from-to)70-85
Number of pages16
JournalNature Metabolism
Volume1
Issue number1
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Internal Medicine
  • Cell Biology
  • General Medicine

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