Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer
Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer
复制标题
DOI：
10.1073/pnas.1304318110
复制
发表时间：
2013-07-09
影响因子：
11.1
通讯作者：
Saatcioglu, Fahri
中科院分区：
文献类型：
--
作者：
Jin, Yang;Qu, Su;Saatcioglu, Fahri
雄激素受体 (AR) 和磷酸肌醇 3-激酶 (PI3K)/蛋白激酶 B/哺乳动物雷帕霉素靶标 (mTOR) 信号传导是许多组织中的两个主要增殖途径，也是包括前列腺癌 (PCa) 在内的各种疾病的主要治疗靶点。先前的工作表明，PCa 中 PI3K 和 AR 信号传导存在相互反馈调节，这表明共同靶向这两种途径可能会增强治疗效果。在这里，我们展示了由两个雄激素调节基因激肽释放酶相关肽酶 4 (KLK4) 和早幼粒细胞白血病锌指 (PLZF) 编码的蛋白质，整合了 PCa 细胞中 AR 和 mTOR 信号传导的最佳功能。 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 还激活发育和 DNA 损伤反应调节 1（mTORC1 的抑制剂）的表达。因此，产生了调节 AR 和 PI3K 信号传导的独特分子开关。一致地，KLK4 敲低导致 PCa 细胞在体外和体内增殖显着下降，减少锚定非依赖性生长，诱导细胞凋亡，并使 PCa 细胞对细胞凋亡诱导剂显着敏感。此外，在携带 PCa 肿瘤的小鼠中体内纳米脂质体 KLK4 siRNA 递送可导致深度缓解。这些结果表明，AR 和 mTOR 通路的活性由 KLK4 维持，因此可能是可行的治疗靶点。
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.