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.
Street
Catharine A
CA
Ghosh Science and Technology Center, Worcester State College, Worcester, MA 01602-2597, USA.
Routhier
Alissa A
AA
Spencer
Carrie
C
Perkins
Ashley L
AL
Masterjohn
Katherine
K
Hackathorn
Alexander
A
Montalvo
John
J
Dennstedt
Emily A
EA
Bryan
Brad A
BA
D000577:Amides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
D000577:Amides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; C108830:Y 27632; D054460:rho-Associated Kinases; D002945:Cisplatin