前列腺癌
雄激素受体
LNCaP公司
癌症研究
柠檬酸循环
生物
线粒体
脂肪生成
内分泌学
内科学
细胞生物学
脂质代谢
癌症
新陈代谢
医学
作者
David A. Bader,Sean M. Hartig,Vasanta Putluri,Christopher Foley,Mark Hamilton,Eric A. Smith,Pradip Kumar Saha,Anil K. Panigrahi,Christopher M. Walker,Lin Zong,Heidi Martini‐Stoica,Rui Chen,Kimal Rajapakshe,Cristian Coarfa,Arun Sreekumar,Nicholas Mitsiades,James A. Bankson,Michael Ittmann,Bert W. O’Malley,Nagireddy Putluri,Sean E. McGuire
标识
DOI:10.1038/s42255-018-0002-y
摘要
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. The metabolic dependencies of androgen receptor (AR)-driven growth in prostate adenocarcinoma are largely unknown but could represent a therapeutic target when hormonal manipulations fail. Here the authors demonstrate that the mitochondrial pyruvate carrier (MPC) is transcriptionally regulated by AR and that MPC inhibition suppresses tumour growth in hormone-responsive and castrate-resistant conditions.
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