Institute of Human Genetics, Jena University Hospital, Jena, Germany.
Int J Cancer. 2019 Apr 15;144(8):1775-1779. doi: 10.1002/ijc.31818. Epub 2018 Nov 4.
The androgen receptor (AR) plays a central role in the pathogenesis of prostate cancer (PCa). Most PCa cases develop eventually from an androgen-dependent stage to castration-resistant prostate cancer (CRPC) with AR-signaling still being active. Thus, inhibition of AR remains a well-established promising drug target in CRPC. However, despite the improvements of current treatment for CRPC by targeting the AR, the evolution of adaptive AR-signaling leads to therapy-resistant CRPC. Treatment failure is based mostly on the inability to keep AR under long-term restraint due to adaptive responses of AR-signaling. One underlying mechanism appears to be the increased AR protein stability. Therefore, the regulation of AR protein stability and its degradation is another interesting path that could enhance our knowledge of carcinogenesis and tumor evolution possibly leading to novel therapeutic targets. In this review, we discuss various molecular mechanisms and factors that stabilize AR protein levels directly or indirectly. We summarize novel approaches to interfere with AR stability including targeting the glucocorticoid receptor (GR), heat shock proteins, and co-chaperones as well as E3-ligases using small chimeric molecules. These novel approaches in combination with antiandrogen treatment inhibit PCa growth through the regulation of AR protein levels.
雄激素受体 (AR) 在前列腺癌 (PCa) 的发病机制中起着核心作用。大多数 PCa 病例最终从雄激素依赖性阶段发展为去势抵抗性前列腺癌 (CRPC)，尽管 AR 信号仍然活跃。因此，抑制 AR 仍然是 CRPC 中一个成熟的有前途的药物靶点。然而，尽管通过靶向 AR 改善了当前治疗 CRPC 的方法，但适应性 AR 信号的进化导致了治疗抵抗性 CRPC。治疗失败主要基于由于 AR 信号的适应性反应而无法长期抑制 AR 的能力。一个潜在的机制似乎是 AR 蛋白稳定性的增加。因此，AR 蛋白稳定性及其降解的调节是另一个有趣的途径，它可能增强我们对致癌作用和肿瘤进化的认识，从而可能导致新的治疗靶点。在这篇综述中，我们讨论了直接或间接稳定 AR 蛋白水平的各种分子机制和因素。我们总结了通过靶向糖皮质激素受体 (GR)、热休克蛋白和共伴侣以及使用小嵌合分子的 E3 连接酶来干扰 AR 稳定性的新方法。这些新方法与抗雄激素治疗相结合，通过调节 AR 蛋白水平抑制 PCa 生长。
