Differential regulation of p21waf1 protein half-life by DNA damage and Nutlin-3 in p53 wild-type tumors and its therapeutic implications

Abstract

DNA damage induces the canonical p53 pathway including elevation of p21waf1 resulting in arrest of cell cycle progression. This can protect cells from subsequent Chk1 inhibition. Some p53 wild-type cancer cells such as HCT116 and U2OS exhibit attenuated p21waf1 induction upon DNA damage due to translational inhibition, and are incapable of maintaining arrest upon Chk1 inhibition. The purpose of this study was to determine whether this attenuated p21waf1 induction also occurred with the non-DNA damaging agent Nutlin-3 which induces p53 by disrupting binding to its negative regulator MDM2. We find that Nutlin-3 circumvented the attenuated induction of p21 waf1 protein by increasing its half-life which led to G1 and G2 arrest in both cell lines. Interestingly, the p21 waf1 protein half-life remained short on Nutlin-3 in p53 wild-type MCF10A cells; these cells achieve high p21waf1 levels through transcriptional upregulation. Consequently, all three p53 wild-type cells but not p53 mutant MDA-MB-231 cancer cells were protected from subsequent incubation with a combination of DNA damage plus a checkpoint inhibitor. © 2012 Landes Bioscience.