p53 Affects PGC1α Stability Through AKT/GSK-3β to Enhance Cisplatin Sensitivity in Non-Small Cell Lung Cancer.

Drug resistance greatly limits the therapeutic efficacy of treatment of non-small cell lung cancer (NSCLC). One of the important factors is the dysfunction of tumor suppressor p53. Recent studies have suggested that p53 suppresses tumors by regulating number of mitochondrial proteins, including peroxisome proliferator-activated receptor coactivator (PGC1 alpha). Although several studies have confirmed the interaction between p53 and PGC1 alpha, the precise mechanism has not been completely determined in NSCLC. In this study, we investigated the specific signaling between p53 and PGC1 alpha to improve anti-tumor drug effects on NSCLC. We found that low expression of p53 and high expression of PGC1 alpha correlated with shorter survival time of NSCLC patients.In vitroexperiments confirmed that NCI-H1299 (p53-null) cells had high levels of PGC1 alpha and were insensitive to cisplatin (CDDP). When PGC1 alpha was knocked down, the sensitivity to cisplatin was increased. Notably, the stability of PGC1 alpha is an important mechanism in its activity regulation. We demonstrated that p53 decreased the stability of PGC1 alpha via the ubiquitin proteasome pathway, which was mediated by protein kinase B (AKT) inhibition and glycogen synthase kinase (GSK-3 beta) activation. Therefore, p53 may regulate the stability of PGC1 alpha through the AKT/GSK-3 beta pathway, thus affect the chemosensitivity of NSCLC.