CDK5RAP3 acts as a tumor suppressor in gastric cancer through inhibition of β-catenin signaling

CDK5RAP3 was isolated as a binding protein of the Cdk5 activator p35. Although CDK5RAP3 has been implicated in cancer progression, its expression and function have not been investigated in gastric cancer. Our study demonstrated that the mRNA and protein levels of CDK5RAP3 were markedly decreased in gastric tumor tissues when compared with respective adjacent non-tumor tissues. CDK5RAP3 in gastric cancer cells significantly reduced cell proliferation, migration, invasion and tumor xenograft growth through inhibition of beta-catenin. Secondly, CDK5RAP3 was found to suppress the phosphorylation of GSK-3 beta (Ser9), leading to the phosphorylation (Ser37/Thr41) and subsequent degradation of beta-catenin. Lastly, the prognostic value of CDK5RAP3 for overall survival was found to be dependent on beta-catenin cytoplasm/nucleus localization in human gastric cancer samples. Collectively, our results demonstrated that CDK5RAP3 negatively regulates the beta-catenin signaling pathway by repressing GSK-3 beta phosphorylation and could be a potential therapeutic target for gastric cancer. (C) 2016 Elsevier Ireland Ltd. All rights reserved.