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 signaling prevents
cell cycle progression while coordinating salvage efforts, chiefly enhanced
glutamine assimilation into the TCA, to regain metabolic homeostasis. We confirm
that MPC function is operant in PCa tumors
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 tumor growth in hormone-responsive and
castrate-resistant conditions. Collectively, our findings characterize the MPC
as a tractable therapeutic target in AR-driven prostate tumors.