Chaperone-mediated autophagy promotes PCa survival during ARPI through selective proteome remodeling

Defining acute stress response mechanisms that mediate prostate cancer (PCa) treatment resistance will help improve therapeutic outcomes of patients treated with androgen receptor pathway inhibition (ARPI). ARPI causes abrupt environmental changes, subjecting PCa cells to acute metabolic stress. We identified the up-regulation of chaperone-mediated autophagy (CMA) in response to acute ARPI stress, which persisted in castration-resistant PCa (CRPC). CMA is a selective protein degradation pathway and a key stress response mechanism up-regulated under several stress stimuli, including metabolic stress. As mediator of selective protein degradation, CMA orchestrates cellular pathway changes mediating the cellular stress response. Broad-spectrum proteomic analysis identified CMA induced proteome remodeling acutely after ARPI stress. CMA sustained PCa growth and survival during ARPI, promoting metabolic reprogramming through the upregulation mTORC1 signaling and pathways associated with PCa biosynthesis and energetics. The upregulation of CMA promotes PCa cell proliferation after ARPI, and emergence of CRPC in-vivo. CMA inhibition compromised PCa metabolism, leading to ATP depletion and profound anti-proliferative effects on PCa cells, enhanced when combined with ARPI. CMA inhibition prevented in-vivo tumour formation, while also re-sensitizing enzalutamide-resistant cell lines in-vitro. The profound anti-proliferative effect of CMA inhibition was attributed to cell cycle arrest mediated through p53 transcriptional repression of E2F target genes. This study established CMA as an acute ARPI stress response mechanism, essential in alleviating ARPI induced metabolic stress to promote PCa growth and survival. CMA plays a critical role in the development of ARPI resistance in PCa.

阐明介导前列腺癌（prostate cancer, PCa）治疗抵抗的急性应激反应机制，将有助于改善接受雄激素受体通路抑制（androgen receptor pathway inhibition, ARPI）治疗的患者的治疗结局。ARPI会引发剧烈的微环境变化，使前列腺癌细胞遭受急性代谢应激。本研究发现，分子伴侣介导的自噬（chaperone-mediated autophagy, CMA）在响应急性ARPI应激时会上调，且该现象在去势抵抗性前列腺癌（castration-resistant PCa, CRPC）中持续存在。分子伴侣介导的自噬是一种选择性蛋白质降解通路，也是包括代谢应激在内的多种应激刺激下被上调的关键应激反应机制。作为选择性蛋白质降解的介导因子，CMA可调控细胞通路的重塑，进而介导细胞应激反应。广谱蛋白质组学分析显示，ARPI应激后，CMA可快速诱导蛋白质组重塑。在ARPI治疗期间，CMA可维持前列腺癌细胞的生长与存活，并通过上调雷帕霉素复合物1（mTORC1）信号通路以及与前列腺癌生物合成和能量代谢相关的通路，促进代谢重编程。CMA的上调可促进ARPI治疗后前列腺癌细胞的增殖，并在体内促进去势抵抗性前列腺癌的发生。抑制CMA会损害前列腺癌细胞的代谢，导致ATP耗竭，并对前列腺癌细胞产生显著的抗增殖作用，且该效应在与ARPI联合使用时会进一步增强。抑制CMA可阻止体内肿瘤形成，同时还能在体外恢复恩扎卢胺（enzalutamide）耐药细胞系的药物敏感性。抑制CMA所产生的显著抗增殖效应，可归因于p53对E2F靶基因的转录抑制所介导的细胞周期阻滞。本研究证实，CMA是一种急性ARPI应激反应机制，在缓解ARPI诱导的代谢应激以促进前列腺癌生长与存活的过程中发挥不可或缺的作用。CMA在前列腺癌ARPI抵抗的发生发展中扮演关键角色。