Department of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC V5Z 4E6, Canada.
The Vancouver Prostate Centre, 2775 Laurel Street, 6th Floor, Vancouver, BC V5Z 1M9, Canada.
Nat Rev Urol. 2015 Jan;12(1):26-36. doi: 10.1038/nrurol.2014.320. Epub 2014 Dec 16.
The survival of malignant cells is constantly threatened by a myriad of cellular insults. In the context of such proteotoxic stress, cancer cells activate cytoprotective adaptive pathways. Heat shock proteins (HSPs) are highly conserved molecular chaperones that are expressed at low levels under normal conditions, but upregulated by cellular stress. As molecular chaperones, HSPs control the stability and function of client proteins, preventing aggregation of misfolded proteins, facilitating intracellular protein trafficking, maintaining protein conformation to enable ligand binding, phosphorylating proteins in signalling complexes and degrading severely damaged proteins via the ubiquitin-proteasome pathway. A key client protein of several HSPs is the androgen receptor (AR). HSPs facilitate binding of dihydrotestosterone to the AR, and enhance AR-mediated transcriptional activity. The integral role of HSPs in AR function speaks to their potential utility as therapeutic targets in castration-resistant prostate cancer (CRPC), a disease state characterized by persistent activation of the androgen-AR axis. Inhibition of HSPs has the additional benefit of potentially modulating signalling and transcriptional networks that are associated with HSP client proteins in CRPC cells. As a consequence, HSPs represent highly attractive targets in the development of treatments for CRPC.
恶性细胞的生存不断受到各种细胞损伤的威胁。在这种蛋白毒性应激的情况下，癌细胞会激活细胞保护适应性途径。热休克蛋白（HSPs）是高度保守的分子伴侣，在正常情况下表达水平较低，但在细胞应激下上调。作为分子伴侣，HSPs 控制着客户蛋白的稳定性和功能，防止错误折叠蛋白的聚集，促进细胞内蛋白运输，维持蛋白构象以允许配体结合，磷酸化信号复合物中的蛋白，并通过泛素-蛋白酶体途径降解严重受损的蛋白。几种 HSP 的关键客户蛋白是雄激素受体（AR）。HSPs 促进二氢睾酮与 AR 的结合，并增强 AR 介导的转录活性。HSPs 在 AR 功能中的重要作用表明，它们有可能成为去势抵抗性前列腺癌（CRPC）的治疗靶点，这种疾病状态的特征是雄激素-AR 轴持续激活。抑制 HSPs 还有可能调节与 CRPC 细胞中 HSP 客户蛋白相关的信号和转录网络。因此，HSPs 是开发治疗 CRPC 方法的极具吸引力的靶点。
