p16(Ink4a) tumor suppressor function in lung cancer cells involves cyclin-dependent kinase 2 inhibition by cip/kip protein redistribution

As cell cycle regulators whose activity is frequently altered in human canc ers, cyclin-dependent kinases (cdks) are novel targets for therapeutic inte rvention. cdk inhibition is an emerging strategy for the treatment of non-s mall cell lung carcinomas (NSCLCs) because most derived cell lines express functional retinoblastoma protein (Rb) but appear to bypass its function wi th inappropriate cdk activity. Elevated cdk4/cdk6 activity in NSCLC cells i s often due to inactivation of the p16(Ink4a) cdk inhibitor. To model the e ffects of cdk4/cdk6 inhibition, we have expressed p16(Ink4a) in a Rb-positi ve NSCLC cell line that lacks endogenous p16(Ink4a) expression. Whereas cdk 4/cdk6 inhibition and Rb dephosphorylation are expected on p16(Ink4a) expre ssion, we have also observed indirect cdk2 inhibition, cdk2 inactivation by the redistribution of other cdk inhibitors may be required for p16(Ink4a)- mediated growth suppression of Rb-positive cells. The implications of such a requirement on the use of chemical cdk inhibitors to treat human cancers will be discussed.