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

David A Bader1, Sean M Hartig1,2, Vasanta Putluri1,3

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

Nature Metabolism
|June 15, 2019
PubMed

Insights

Researchers found that inhibiting the mitochondrial pyruvate carrier (MPC) slows prostate cancer growth by disrupting its metabolism. This discovery identifies the MPC as a potential therapeutic target for prostate adenocarcinoma (PCa).

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • Androgen receptor (AR)-driven prostate adenocarcinoma (PCa) growth relies on specific metabolic pathways that are not fully understood.
  • Targeting metabolic dependencies is crucial, especially when hormonal therapies fail.

Purpose of the Study:

  • To investigate the role of the mitochondrial pyruvate carrier (MPC) in AR-driven PCa.
  • To explore MPC inhibition as a therapeutic strategy for prostate cancer.

Main Methods:

  • Investigated AR-mediated transcriptional regulation of MPC.
  • Utilized experimental MPC inhibition in AR-driven PCa models.
  • Performed isotopomeric metabolic flux analysis in PCa tumors.
  • Tested a small molecule MPC inhibitor (MSDC0160) in pre-clinical models.

Main Results:

  • AR transcriptionally regulates the mitochondrial pyruvate carrier (MPC).
  • MPC inhibition restricts PCa cell proliferation and key metabolic outputs like the citric acid cycle (TCA) and oxidative phosphorylation.
  • Metabolic disruption activates the integrated stress response (ISR), which halts cell cycle progression.
  • MPC inhibition suppresses tumor growth in both hormone-responsive and castrate-resistant PCa models.

Conclusions:

  • The mitochondrial pyruvate carrier (MPC) is a critical metabolic vulnerability in AR-driven prostate cancer.
  • Targeting the MPC, for example with MSDC0160, shows promise for treating prostate adenocarcinoma.
  • MPC inhibition represents a tractable therapeutic strategy for AR-driven prostate tumors.

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