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: C Zhang, S Zhang, Z Zhang, J He, Y Xu, S Liu
• Journal: Oncogene (Oncogene) Vol. 33 Issue 49 Pg. 5582-91 (Dec 04 2014) ISSN: 1476-5594 [Electronic] England
• PMID: 24317511 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• MIR17HG, human
• MYC protein, human
• MicroRNAs
• NOP16 protein, human
• Proteins
• Proto-Oncogene Proteins c-myc
• Pyridines
• RNA, Long Noncoding
• RNA, Messenger
• RNA, Small Interfering
• Y 27632
• ROCK1 protein, human
• rho-Associated Kinases

Topics

• Amides (chemistry)
• Animals
• Breast Neoplasms (metabolism)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cytoskeleton (metabolism)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (metabolism)
• Microscopy, Confocal
• Mutagenesis
• Phosphorylation
• Prostatic Neoplasms (metabolism)
• Proteins (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• Pyridines (chemistry)
• RNA, Long Noncoding
• RNA, Messenger (metabolism)
• RNA, Small Interfering (metabolism)
• Signal Transduction
• rho-Associated Kinases (physiology)