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.

RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates fasudil as an antileukemic drug

“…Application of ROCK1 inhibitors reduced the metastatic potential in cells from several kinds of solid tumors, presumably by decreasing cell motility. 39,40 This mechanism is unlikely to explain the observed activity of ROCK1 inhibition in our feeder-free AML suspension-culture experiments. However, the destabilization of c-MYC, observed in ROCK inhibitor-treated prostate cancer cells, 39 might have played a role because this oncogene is frequently deregulated in AML.…”

“…39,40 This mechanism is unlikely to explain the observed activity of ROCK1 inhibition in our feeder-free AML suspension-culture experiments. However, the destabilization of c-MYC, observed in ROCK inhibitor-treated prostate cancer cells, 39 might have played a role because this oncogene is frequently deregulated in AML. 41 Although the precise mode of action by which ROCK1 inhibition reduced leukemic burden in our in vitro and in vivo experiments was beyond the focus of our research, our results suggest that further exploration of ROCK1 inhibition as a potential antileukemic strategy is warranted.…”

Gα13/PDZ-RhoGEF/RhoA Signaling Is Essential for Gastrin-Releasing Peptide Receptor–Mediated Colon Cancer Cell Migration

“…Increased RhoA activation and signaling through its downstream effectors, such as Rho-associated kinase (ROCK), contributes to cancer progression. Activation of the RhoA-ROCK signaling axis initiates cytoskeletal changes that are essential for cancer cell motility and invasion, initiates gene transcription, and promotes cancer cell proliferation (Yagi et al, 2011;Vigil et al, 2012;Zhang et al, 2013). It is currently unknown if GRPR-mediated RhoA-ROCK signaling plays a role in regulation of colon cancer cell migration.…”

An important role of the hepcidin–ferroportin signaling in affecting tumor growth and metastasis

“…Cell cycle progression was determined following a standard protocol described in our previous study [20]. Briefly, after treatments, cells were washed with PBS, and then fixed in 70% ethanol overnight.…”