Fig. 14.
Proposed possible mechanism by which the PKD inhibitor CRT0066101 suppresses bladder cancer growth through blocking cell cycle progression at the G2/M phase. This schematic diagram shows that PKD2 inhibition by CRT0066101 treatment activates the kinase Chk1 through a yet-to-be-defined mechanism, thereby preventing from the activation of the downstream stimulatory phosphatase Cdc25C leading to decreased the CDK1-cyclin B1 complex activity. On the other hand, Chk1 kinase also reduces CDK1-cyclin B1 activity by activating the inhibitory kinases Myt1 and Wee1 through phosphorylating CDK1 at Thr14 and Tyr15. In addition, CRT0066101 modulates several other regulators of the G2/M transition involving regulation of CDK1, including p27Kip1, Gadd45α, 14-3-3σ, and other isoforms of 14-3-3 proteins. All of the regulators may act cooperatively and collaboratively to suppress the proliferation of bladder tumor cells through regulating CDK1 and the cell cycle G2 checkpoint. Such a mechanism may serve to integrate the roles of these regulators in culmination in G2/M arrest and cell cycle block, which may underlie the mechanism of CRT0066101-mediated tumor growth suppression of bladder urothelial cell carcinoma. See “Discussion” for further elaboration. T14 threonine 14, Y15 tyrosine 15