ERRα通过直接调控柠檬酸代谢和锌转运，控制前列腺癌细胞的干性和细胞能量代谢

雌激素相关受体α（ERRα）通过直接调控柠檬酸代谢和锌转运，控制前列腺癌细胞的干性和细胞能量代谢

Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation

作者:Taiyang Ma, Wenjuan Xie, Zhenyu Xu, Weijie Gao, Jianfu Zhou, Yuliang Wang, Franky Leung Chan

期刊:Cell Death & Disease

摘要

与大多数更偏向糖酵解的肿瘤不同，原发性前列腺癌的糖酵解水平较低，但更依赖TCA循环结合OXPHOS以满足能量需求。这一独特的代谢特征归因于线粒体m-aconitase在TCA中的激活，主要由细胞锌（Zn）水平降低引起。有证据显示，前列腺肿瘤中的一个小亚群细胞，即前列腺癌干细胞（PCSCs），在晚期前列腺癌的进展中扮演重要角色，但其细胞能量状态尚不清楚。核受体ERRα（ESRRA）是能量代谢的关键调控因子。既往研究表明，ERRα在前列腺癌中上调，具有多种促癌功能。在本研究中，我们展示了ERRα在调控PCSCs的干性和能量代谢中的新作用，机制包括通过转录抑制锌转运蛋白ZIP1，减少细胞内Zn的摄取，以及转激活ACO2（m-aconitase）以完成TCA循环。结果还表明，使用锌离子载体Clioquinol恢复锌积累，可以显著抑制PCSCs的体外生长及其体内肿瘤形成，提示增强细胞内锌摄取可能成为靶向晚期前列腺癌中PCSCs的潜在治疗策略。

Abstract

Compared to most tumors that are more glycolytic, primary prostate cancer is less glycolytic but more dependent on TCA cycle coupled with OXPHOS for its energy demand. This unique metabolic energetic feature is attributed to activation of mitochondrial m-aconitase in TCA caused by decreased cellular Zn level. Evidence suggests that a small subpopulation of cancer cells within prostate tumors, designated as prostate cancer stem cells (PCSCs), play significant roles in advanced prostate cancer progression. However, their cellular energetics status is still poorly understood. Nuclear receptor ERRα (ESRRA) is a key regulator of energy metabolism. Previous studies characterize that ERRα exhibits an upregulation in prostate cancer and can perform multiple oncogenic functions. Here, we demonstrate a novel role of ERRα in the control of stemness and energetics metabolism in PCSCs via a mechanism of combined transrepression of Zn transporter ZIP1 in reducing intracellular Zn uptake and transactivation of ACO2 (m-aconitase) in completion of TCA cycle. Results also showed that restoration of Zn accumulation by treatment with a Zn ionophore Clioquinol could significantly suppress both in vitro growth of PCSCs and also their in vivo tumorigenicity, implicating that enhanced cellular Zn uptake could be a potential therapeutic approach for targeting PCSCs in advanced prostate cancer.

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