Rho kinase proteins--pleiotropic modulators of cell survival and apoptosis.

Rho kinase (ROCK) proteins are Rho-GTPase activated serine/threonine kinases that function as modulators of actin-myosin cytoskeletal dynamics via regulation of Lin11, Isl-1 & Mec-3 domain (LIM) kinase, myosin light chain (MLC), and MLC phosphatase. A strong correlation between cytoskeletal rearrangements and tumor cell invasion, metastasis, and deregulated microenvironment interaction has been reported in the literature, and the utilization of pharmacological inhibitors of ROCK signaling for the treatment of cancer is actively being pursued by a number of pharmaceutical companies. Indeed, in many preclinical models ROCK inhibitors have shown remarkable efficacy in reducing tumor growth and metastasis. Interestingly, ROCK signaling has been shown to be either pro-apoptotic or pro-survival in a cell type and context dependent manner, though the molecular mechanisms controlling ROCK-mediated cell fate decisions are unknown. This review summarizes the many pleiotropic roles of ROCK signaling in survival and apoptosis, and suggests that controlled modulation of ROCK activity in tumor cells has the potential to significantly affect tumor survival and patient outcome.

Pharmacological inhibition of Rho-kinase (ROCK) signaling enhances cisplatin resistance in neuroblastoma cells.

The role of the RhoA/Rho kinase (ROCK) signaling pathway in cell survival remains a very controversial issue, with its activation being pro-apoptotic in many cell types and anti-apoptotic in others. To test if ROCK inhibition contributes to tumor cell survival or death following chemotherapy, we treated cisplatin damaged neuroblastoma cells with a pharmacological ROCK inhibitor (Y27632) or sham, and monitored cell survival, accumulation of a chemoresistant phenotype, and in vivo tumor formation. Additionally, we assayed if ROCK inhibition altered the expression of genes known to be involved in cisplatin resistance. Our studies indicate that ROCK inhibition results in increased cell survival, acquired chemoresistance, and enhanced tumor survival following cisplatin cytotoxicity, due in part to altered expression of cisplatin resistance genes. These findings suggest that ROCK inhibition in combination with cisplatin chemotherapy may lead to enhanced tumor chemoresistance in neuroblastoma.