Small molecule inhibition of cytoskeletal dynamics in melanoma tumors results in altered transcriptional expression patterns of key genes involved in tumor initiation and progression.

BACKGROUND: Rho kinase signaling plays an important role in the oncogenic process largely through its regulation of F-actin dynamics, and inhibition of this pathway results in reduction in tumor volume and metastasis across a number of tumor types. While the cytoskeletal-regulatory role of Rho kinase has been a topic of in-depth study, the mechanisms linking Rho kinase to altered gene expression are largely unknown. MATERIALS AND METHODS: Global gene expression analysis was performed on melanoma tumors treated with sham or the small molecule inhibitor Y27632. RESULTS: Inhibition of Rho kinase activity in melanoma tumors results in a statistically significant change in gene transcription of 94 genes, many of which are critically involved in tumor initiation and progression. CONCLUSION: In addition to regulating tumorigenesis through modulation of the phosphoproteome, Rho kinase signaling also contributes to the regulation of the tumor transcriptome.

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.