ROCK has a crucial role in regulating prostate tumor growth through interaction with c-Myc
ROCK has a crucial role in regulating prostate tumor growth through interaction with c-Myc
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ROCK 通过与 c-Myc 相互作用在调节前列腺肿瘤生长方面发挥着至关重要的作用
作者：
Zhang Z;He J;Xu Y;Liu S.
Rho相关激酶（ROCK）在控制细胞形态和运动中具有重要作用，并且ROCK活性增加有助于癌细胞侵袭和转移。新兴的数据表明，ROCK也参与肿瘤细胞的生长调节。然而，到目前为止，负责ROCK控制的肿瘤细胞生长的分子机制尚未明确阐明。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或通过特定的ROCK小干扰RNA（siRNA）分子，衰减不仅运动，而且在体外和体内的PC 3前列腺癌细胞的增殖。重要的是，机制研究表明，ROCK赋予癌细胞致瘤能力，主要是通过靶向c-Myc。ROCK可通过促进c-Myc蛋白的稳定性来增加c-Myc的转录活性，并且ROCK抑制可减少c-Myc介导的mRNA靶点（如HSPC 111）和microRNA靶点（如miR-17-92簇）的表达。我们提供的证据表明，ROCK 1直接与c-Myc相互作用并磷酸化，导致蛋白质的稳定和转录活性的激活。抑制ROCK-c-Myc下游分子，如c-Myc调节的miR-17，也会在体外和体内损害肿瘤细胞生长。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及其刺激的信号传导可能被证明是抑制前列腺癌肿瘤进展的有希望的策略。
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.
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影响因子：
5.3
作者：
A. Seth;Shashi Gupta;Roger J. Davis
通讯作者：
A. Seth;Shashi Gupta;Roger J. Davis
影响因子：
50.3
作者：
Taylor BS;Schultz N;Hieronymus H;Gopalan A;Xiao Y;Carver BS;Arora VK;Kaushik P;Cerami E;Reva B;Antipin Y;Mitsiades N;Landers T;Dolgalev I;Major JE;Wilson M;Socci ND;Lash AE;Heguy A;Eastham JA;Scher HI;Reuter VE;Scardino PT;Sander C;Sawyers CL;Gerald WL
通讯作者：
Gerald WL
DOI：
10.1016/s0021-9258(18)98613-8
发表时间：
1991-08
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Elvira Alvarez;I. Northwood;F. Gonzalez;Debra A. Latour;A. Seth;C. Abate;T. Curran;R. Davis
通讯作者：
Elvira Alvarez;I. Northwood;F. Gonzalez;Debra A. Latour;A. Seth;C. Abate;T. Curran;R. Davis
影响因子：
64.8
作者：
Uehata, M;Ishizaki, T;Narumiya, S
通讯作者：
Narumiya, S
DOI：
10.3760/cma.j.issn.0253-3766.2011.03.011
发表时间：
2011-03
期刊：
Zhonghua zhong liu za zhi [Chinese journal of oncology]
影响因子：
--
作者：
Qiang Bu;Huaming Tang;Jian Tan;Xiao Hu;Dong-wen Wang
通讯作者：
Qiang Bu;Huaming Tang;Jian Tan;Xiao Hu;Dong-wen Wang