Shah Supriya, Carriveau Whitney J, Li Jinyang, Campbell Sydney L, Kopinski Piotr K, Lim Hee-Woong, Daurio Natalie, Trefely Sophie, Won Kyoung-Jae, Wallace Douglas C, Koumenis Constantinos, Mancuso Anthony, Wellen Kathryn E
Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Oncotarget. 2016 Jul 12;7(28):43713-43730. doi: 10.18632/oncotarget.9666.
The androgen receptor (AR) plays a central role in prostate tumor growth. Inappropriate reactivation of the AR after androgen deprivation therapy promotes development of incurable castration-resistant prostate cancer (CRPC). In this study, we provide evidence that metabolic features of prostate cancer cells can be exploited to sensitize CRPC cells to AR antagonism. We identify a feedback loop between ATP-citrate lyase (ACLY)-dependent fatty acid synthesis, AMPK, and the AR in prostate cancer cells that could contribute to therapeutic resistance by maintaining AR levels. When combined with an AR antagonist, ACLY inhibition in CRPC cells promotes energetic stress and AMPK activation, resulting in further suppression of AR levels and target gene expression, inhibition of proliferation, and apoptosis. Supplying exogenous fatty acids can restore energetic homeostasis; however, this rescue does not occur through increased β-oxidation to support mitochondrial ATP production. Instead, concurrent inhibition of ACLY and AR may drive excess ATP consumption as cells attempt to cope with endoplasmic reticulum (ER) stress, which is prevented by fatty acid supplementation. Thus, fatty acid metabolism plays a key role in coordinating ER and energetic homeostasis in CRPC cells, thereby sustaining AR action and promoting proliferation. Consistent with a role for fatty acid metabolism in sustaining AR levels in prostate cancer in vivo, AR mRNA levels in human prostate tumors correlate positively with expression of ACLY and other fatty acid synthesis genes. The ACLY-AMPK-AR network can be exploited to sensitize CRPC cells to AR antagonism, suggesting novel therapeutic opportunities for prostate cancer.
雄激素受体（AR）在前列腺肿瘤生长中起核心作用。雄激素剥夺治疗后AR的不适当重新激活会促进难以治愈的去势抵抗性前列腺癌（CRPC）的发展。在本研究中，我们提供证据表明，前列腺癌细胞的代谢特征可被利用来使CRPC细胞对AR拮抗作用敏感。我们在前列腺癌细胞中发现了ATP柠檬酸裂解酶（ACLY）依赖性脂肪酸合成、AMPK和AR之间的反馈回路，该回路可能通过维持AR水平导致治疗抵抗。当与AR拮抗剂联合使用时，CRPC细胞中ACLY的抑制会促进能量应激和AMPK激活，从而进一步抑制AR水平和靶基因表达，抑制增殖并诱导凋亡。提供外源性脂肪酸可恢复能量稳态；然而，这种挽救并非通过增加β-氧化以支持线粒体ATP产生来实现。相反，ACLY和AR的同时抑制可能会导致细胞在试图应对内质网（ER）应激时消耗过多ATP，而脂肪酸补充可防止这种情况发生。因此，脂肪酸代谢在协调CRPC细胞中的内质网和能量稳态中起关键作用，从而维持AR作用并促进增殖。与脂肪酸代谢在体内维持前列腺癌中AR水平的作用一致，人类前列腺肿瘤中的AR mRNA水平与ACLY和其他脂肪酸合成基因的表达呈正相关。ACLY-AMPK-AR网络可被利用来使CRPC细胞对AR拮抗作用敏感，这为前列腺癌提示了新的治疗机会。
