Department of Biosciences, University of Oslo, 0316 Oslo, Norway.
Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):E2572-81. doi: 10.1073/pnas.1304318110. Epub 2013 Jun 24.
The androgen receptor (AR) and the phosphoinositide 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin (mTOR) signaling are two of the major proliferative pathways in a number of tissues and are the main therapeutic targets in various disorders, including prostate cancer (PCa). Previous work has shown that there is reciprocal feedback regulation of PI3K and AR signaling in PCa, suggesting that cotargeting both pathways may enhance therapeutic efficacy. Here we show that proteins encoded by two androgen-regulated genes, kallikrein related peptidase 4 (KLK4) and promyelocytic leukemia zinc finger (PLZF), integrate optimal functioning of AR and mTOR signaling in PCa cells. KLK4 interacts with PLZF and decreases its stability. PLZF in turn interacts with AR and inhibits its function as a transcription factor. PLZF also activates expression of regulated in development and DNA damage responses 1, an inhibitor of mTORC1. Thus, a unique molecular switch is generated that regulates both AR and PI3K signaling. Consistently, KLK4 knockdown results in a significant decline in PCa cell proliferation in vitro and in vivo, decreases anchorage-independent growth, induces apoptosis, and dramatically sensitizes PCa cells to apoptosis-inducing agents. Furthermore, in vivo nanoliposomal KLK4 siRNA delivery in mice bearing PCa tumors results in profound remission. These results demonstrate that the activities of AR and mTOR pathways are maintained by KLK4, which may thus be a viable target for therapy.
雄激素受体（AR）和磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B/雷帕霉素靶蛋白（mTOR）信号通路是许多组织中两种主要的增殖途径，也是包括前列腺癌（PCa）在内的各种疾病的主要治疗靶点。先前的研究表明，PI3K 和 AR 信号通路在 PCa 中有相互反馈调节作用，这表明同时靶向这两条通路可能会增强治疗效果。在这里，我们发现两个雄激素调节基因，激肽释放酶相关肽 4（KLK4）和早幼粒细胞白血病锌指（PLZF）编码的蛋白整合了 AR 和 mTOR 信号在 PCa 细胞中的最佳功能。KLK4 与 PLZF 相互作用并降低其稳定性。PLZF 反过来与 AR 相互作用并抑制其作为转录因子的功能。PLZF 还激活了 mTORC1 抑制剂发育和 DNA 损伤反应蛋白 1 的表达。因此，生成了一个独特的分子开关，调节 AR 和 PI3K 信号。一致地，KLK4 的敲低导致 PCa 细胞在体外和体内的增殖显著下降，降低了非锚定依赖性生长，诱导细胞凋亡，并显著增强了 PCa 细胞对凋亡诱导剂的敏感性。此外，在携带 PCa 肿瘤的小鼠体内用纳米脂质体 KLK4 siRNA 进行体内给药可导致严重缓解。这些结果表明，AR 和 mTOR 途径的活性由 KLK4 维持，因此 KLK4 可能是一种可行的治疗靶点。
