Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy.
Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy.
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DOI：
10.1038/s41467-018-07411-7
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发表时间：
2018-11-26
影响因子：
16.6
通讯作者：
Qian DZ
中科院分区：
文献类型：
--
作者：
Geng H;Xue C;Mendonca J;Sun XX;Liu Q;Reardon PN;Chen Y;Qian K;Hua V;Chen A;Pan F;Yuan J;Dang S;Beer TM;Dai MS;Kachhap SK;Qian DZ
尽管最近取得了进展，但雄激素/雄激素受体 (AR) 靶向治疗对于许多转移性前列腺癌患者的疗效仍然有限。这部分是因为前列腺癌为了生存和生长而适应性地切换到雄激素/AR独立途径，从而产生治疗耐药性。肿瘤缺氧被认为是治疗抵抗的主要原因。然而，确切的机制很大程度上尚不清楚。在这里，我们报告说，缺氧条件下的慢性雄激素剥夺疗法（ADT）会诱导适应性雄激素/AR独立性，因此赋予雄激素/AR靶向治疗（例如恩杂鲁胺）的抗性。从机制上讲，这是由葡萄糖-6-磷酸异构酶 (GPI) 介导的，在缺氧情况下，GPI 的转录受到 AR 的抑制，但通过 AR 抑制而恢复并增加。反过来，GPI通过将葡萄糖通量从雄激素/AR依赖的磷酸戊糖途径(PPP)重定向至缺氧诱导的糖酵解途径来维持缺氧时的葡萄糖代谢和能量稳态，从而降低恩杂鲁胺的生长抑制作用。抑制 GPI 克服了体外缺氧时的治疗耐药性，并增加了恩杂鲁胺的体内疗效。前列腺癌通常会对雄激素受体 (AR) 靶向药物产生耐药性。在这里，作者表明，在缺氧条件下，通过恩杂鲁胺抑制 AR 会增加糖酵解酶磷酸葡萄糖异构酶 (GPI) 的表达，促进代谢重新布线，从而使细胞能够存活，而持续的 GPI 抑制可以恢复对恩杂鲁胺的敏感性。
Despite recent advances, the efficacy of androgen/androgen receptor (AR)-targeted therapy remains limited for many patients with metastatic prostate cancer. This is in part because prostate cancers adaptively switch to the androgen/AR-independent pathway for survival and growth, thereby conferring therapy resistance. Tumor hypoxia is considered as a major cause of treatment resistance. However, the exact mechanism is largely unclear. Here we report that chronic-androgen deprivation therapy (ADT) in the condition of hypoxia induces adaptive androgen/AR-independence, and therefore confers resistance to androgen/AR-targeted therapy, e.g., enzalutamide. Mechanistically, this is mediated by glucose-6-phosphate isomerase (GPI), which is transcriptionally repressed by AR in hypoxia, but restored and increased by AR inhibition. In turn, GPI maintains glucose metabolism and energy homeostasis in hypoxia by redirecting the glucose flux from androgen/AR-dependent pentose phosphate pathway (PPP) to hypoxia-induced glycolysis pathway, thereby reducing the growth inhibitory effect of enzalutamide. Inhibiting GPI overcomes the therapy resistance in hypoxia in vitro and increases enzalutamide efficacy in vivo. Prostate cancer often develops resistance to androgen receptor (AR) targeting drugs. Here, the authors show that, under conditions of hypoxia, AR inhibition via enzalutamide increases the expression of the glycolytic enzyme phosphoglucose isomerase (GPI) promoting a metabolic rewiring that allows the cells to survive, and consistent GPI inhibition restores sensitivity to enzalutamide.
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