Abstract 4301: Mechanisms underlying the inhibitory effect of CRT0066101 on bladder cancer growth in vitro and in vivo

Abstract

Abstract CRT0066101 is an inhibitor of protein kinase D with anti-tumor activity in several types of human carcinomas. However, the effect and mechanism of CRT0066101 in bladder cancer remain unknown. In this study, we show that CRT0066101 inhibited the proliferation and migration of bladder cancer cells, but had only a marginal effect in human uroepithelial cells, indicating a differential inhibitory effect on cell growth between bladder cancer and normal urothelium. We also demonstrate that CRT0066101 blocked bladder cancer growth in a xenograft flank mouse model. Our cell cycle analysis revealed that CRT0066101 arrested bladder tumor cells at the G2-M phase, the arrest being accompanied by decreases in the levels of cyclin B1 and CDK1 and increases in the levels of p27kip1 and phospho-CDK1 (Thr14/Tyr15). Moreover, CRT0066101 reduced the expression of Cdc25C, which dephosphorylates/activates CDK1, but enhanced the activity of the checkpoint kinase Chk1, which phosphorylates/ inactivates Cdc25C. Finally, CRT0066101 was found to elevate the levels of Myt1, Wee1, phospho-Cdc25C (Ser216), Gadd45α, and 14-3-3 proteins, all of which cause a reduction in CDK1-cyclin B1 activity. Together, these data suggest that CRT0066101 suppresses bladder cancer growth partly through modulating the cell cycle G2 checkpoint and inducing G2-M phase arrest, leading to the blockade of cell cycle progression. Citation Format: Quentin Li, Iawen Hsu, Reema Railkar, Thomas Sanford, Piyush K. Agarwal. Mechanisms underlying the inhibitory effect of CRT0066101 on bladder cancer growth in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4301.