Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, Ohio, USA.
Endocr Relat Cancer. 2020 Jun;27(6):R193-R210. doi: 10.1530/ERC-20-0048.
Prostate cancer (CaP) is the second leading cause of cancer-related deaths in Western men. Because androgens drive CaP by activating the androgen receptor (AR), blocking AR's ligand activation, known as androgen deprivation therapy (ADT), is the default treatment for metastatic CaP. Despite an initial remission, CaP eventually develops resistance to ADT and progresses to castration-recurrent CaP (CRPC). CRPC continues to rely on aberrantly activated AR that is no longer inhibited effectively by available therapeutics. Interference with signaling pathways downstream of activated AR that mediate aggressive CRPC behavior may lead to alternative CaP treatments. Developing such therapeutic strategies requires a thorough mechanistic understanding of the most clinically relevant and druggable AR-dependent signaling events. Recent proteomics analyses of CRPC clinical specimens indicate a shift in the phosphoproteome during CaP progression. Kinases and phosphatases represent druggable entities, for which clinically tested inhibitors are available, some of which are incorporated already in treatment plans for other human malignancies. Here, we reviewed the AR-associated transcriptome and translational regulon, and AR interactome involved in CaP phosphorylation events. Novel and for the most part mutually exclusive AR-dependent transcriptional and post-transcriptional control over kinase and phosphatase expression was found, with yet other phospho-regulators interacting with AR. The multiple mechanisms by which AR can shape and fine-tune the CaP phosphoproteome were reflected in diverse aspects of CaP biology such as cell cycle progression and cell migration. Furthermore, we examined the potential, limitations and challenges of interfering with AR-mediated phosphorylation events as alternative strategy to block AR function during CaP progression.
前列腺癌（CaP）是西方男性癌症相关死亡的第二大原因。由于雄激素通过激活雄激素受体（AR）来驱动 CaP，阻断 AR 的配体激活，即雄激素剥夺疗法（ADT），是转移性 CaP 的默认治疗方法。尽管最初有缓解，但 CaP 最终会对 ADT 产生耐药性，并发展为去势复发性 CaP（CRPC）。CRPC 仍然依赖于异常激活的 AR，而现有的治疗方法已不再能有效抑制其活性。干扰激活的 AR 下游信号通路，这些信号通路介导侵袭性 CRPC 行为，可能会导致替代的 CaP 治疗方法。开发这种治疗策略需要对最具临床相关性和可成药的 AR 依赖性信号事件有透彻的机制理解。最近对 CRPC 临床标本的蛋白质组学分析表明，在 CaP 进展过程中磷酸化组发生了变化。激酶和磷酸酶是可成药的实体，已有临床测试的抑制剂，其中一些已被纳入其他人类恶性肿瘤的治疗方案中。在这里，我们综述了与 AR 相关的转录组和翻译调节子，以及参与 CaP 磷酸化事件的 AR 相互作用组。发现了新型的、大部分相互排斥的 AR 依赖性转录和转录后控制，以及与 AR 相互作用的其他磷酸化调节剂。AR 可以通过多种机制来塑造和微调 CaP 磷酸化组，这反映在 CaP 生物学的多个方面，如细胞周期进程和细胞迁移。此外，我们还研究了干扰 AR 介导的磷酸化事件作为阻止 CaP 进展过程中 AR 功能的替代策略的潜力、局限性和挑战。
