title: ROCK has a crucial role in regulating prostate tumor growth through interaction with c-Myc.
abstract: 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.
authors: 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.
authors: C
authors: C
authors: Zhang
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
authors: S
authors: S
authors: Zhang
authors: Department of Urology, Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin, China.
authors: Z
authors: Z
authors: Zhang
authors: Department of Biomedical Engineering, Tufts University, Medford, MA, USA.
authors: J
authors: J
authors: He
authors: Department of Urology, Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin, China.
authors: Y
authors: Y
authors: Xu
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
authors: S
authors: S
authors: Liu
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D018613:Microscopy, Confocal; D016296:Mutagenesis; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry; D062085:RNA, Long Noncoding; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000502:physiology*
chemical_list: D000577:Amides; C568997:MIR17HG, human; C489427:MYC protein, human; D035683:MicroRNAs; C530131:NOP16 protein, human; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C108830:Y 27632; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases