1] State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China [2] Department of Urology, Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin, China.
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
Oncogene. 2014 Dec 4;33(49):5582-91. doi: 10.1038/onc.2013.505. Epub 2013 Dec 9.
Rho-associated kinase (ROCK) has an essential role in governing cell morphology and motility, and increased ROCK activity contributes to cancer cell invasion and metastasis. Burgeoning data suggest that ROCK is also involved in the growth regulation of tumor cells. However, thus far, the molecular mechanisms responsible for ROCK-governed tumor cell growth have not been clearly elucidated. Here we showed that inhibition of ROCK kinase activity, either by a selective ROCK inhibitor Y27632 or by specific ROCK small interfering RNA (siRNA) molecules, attenuated not only motility but also the proliferation of PC3 prostate cancer cells in vitro and in vivo. Importantly, mechanistic investigation revealed that ROCK endowed cancer cells with tumorigenic capability, mainly by targeting c-Myc. ROCK could increase the transcriptional activity of c-Myc by promoting c-Myc protein stability, and ROCK inhibition reduced c-Myc-mediated expression of mRNA targets (such as HSPC111) and microRNA targets (such as miR-17-92 cluster). We provided evidence demonstrating that ROCK1 directly interacted with and phosphorylated c-Myc, resulting in stabilization of the protein and activation of its transcriptional activity. Suppression of ROCK-c-Myc downstream molecules, such as c-Myc-regulated miR-17, also impaired tumor cell growth in vitro and in vivo. In addition, c-Myc was shown to exert a positive feedback regulation on ROCK by increasing RhoA mRNA expression. Therefore, inhibition of ROCK and its stimulated signaling might prove to be a promising strategy for restraining tumor progression in prostate cancer.
Rho 相关激酶（ROCK）在调节细胞形态和运动方面起着重要作用，ROCK 活性的增加有助于癌细胞的侵袭和转移。越来越多的数据表明，ROCK 还参与肿瘤细胞的生长调控。然而，到目前为止，负责 ROCK 调控肿瘤细胞生长的分子机制尚未得到明确阐明。在这里，我们表明 ROCK 激酶活性的抑制，无论是通过选择性 ROCK 抑制剂 Y27632 还是通过特定的 ROCK 小干扰 RNA（siRNA）分子，不仅减弱了 PC3 前列腺癌细胞的运动能力，而且减弱了其体外和体内的增殖能力。重要的是，机制研究表明，ROCK 通过靶向 c-Myc 赋予癌细胞致瘤能力。ROCK 可以通过促进 c-Myc 蛋白稳定性来增加 c-Myc 的转录活性，而 ROCK 抑制则降低了 c-Myc 介导的 mRNA 靶标（如 HSPC111）和 microRNA 靶标（如 miR-17-92 簇）的表达。我们提供的证据表明，ROCK1 直接与 c-Myc 相互作用并使其磷酸化，导致蛋白稳定和转录活性激活。抑制 ROCK-c-Myc 下游分子，如 c-Myc 调控的 miR-17，也会损害体外和体内肿瘤细胞的生长。此外，c-Myc 通过增加 RhoA mRNA 表达对 ROCK 发挥正反馈调节作用。因此，抑制 ROCK 及其刺激的信号通路可能被证明是抑制前列腺癌肿瘤进展的一种有前途的策略。
