Ma Taiyang, Xie Wenjuan, Xu Zhenyu, Gao Weijie, Zhou Jianfu, Wang Yuliang, Chan Franky Leung
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
Cell Death Dis. 2025 Mar 5;16(1):154. doi: 10.1038/s41419-025-07460-z.
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.
与大多数糖酵解程度更高的肿瘤相比，原发性前列腺癌的糖酵解程度较低，但在能量需求方面更依赖于与氧化磷酸化偶联的三羧酸循环。这种独特的代谢能量特征归因于细胞内锌水平降低导致三羧酸循环中线粒体顺乌头酸酶的激活。有证据表明，前列腺肿瘤内一小部分癌细胞，即前列腺癌干细胞（PCSCs），在晚期前列腺癌进展中起重要作用。然而，它们的细胞能量状态仍知之甚少。核受体ERRα（ESRRA）是能量代谢的关键调节因子。先前的研究表明，ERRα在前列腺癌中表现出上调，并可发挥多种致癌功能。在此，我们证明了ERRα通过联合反式抑制锌转运蛋白ZIP1以减少细胞内锌摄取以及反式激活ACO2（顺乌头酸酶）以完成三羧酸循环的机制，在控制PCSCs的干性和能量代谢中发挥新作用。结果还表明，用锌离子载体氯碘羟喹治疗恢复锌积累可显著抑制PCSCs的体外生长及其体内致瘤性，这表明增强细胞对锌的摄取可能是靶向晚期前列腺癌中PCSCs的一种潜在治疗方法。
