GSK3β Inhibition Triggers PLK1/P53-Dependent DNA Repair Revealing a Promising Strategy for Ovarian Cancer Treatment

Most ovarian cancer (OC) tumors are P53-mutant with some mutant P53 proteins possesses an oncogenic activity in OC development. Glycogen synthase kinase 3β (GSK3β), an enzyme closely relates to OC development was found to regulate P53 abundance in several cancer cells, however, whether GSK3β regulates P53 protein expression in OC is unknown. We initially aimed to address this issue, which led to identify a novel signaling axis involved in DNA damage repair in OC cell lines. We found GSK3β reversely regulated P53 signaling across ovarian OC cell lines. Inhibition of GSK3β impeded the homogenous recombination (HR) signaling pathway for DNA damage repair thus caused DNA damage, which was responsible for the raised P53 expression in the HR-proficient OC cells. The raised P53, whether mutated or not, attenuated DNA damage caused by GSK3β inhibition. We further confirmed PLK1/Aurora A axis was governed by GSK3β. Inhibition of GSK3β activated PLK1 via Aurora A in ovarian cancer cells and activation of PLK1 related to DNA damage repair. Double inhibition of GSK3β and PLK1 had a synergistic effect on inducing DNA damage and cell apoptosis in OC cells, which stands as a promising therapeutic strategy for OC.