MDM2 up-regulates the energy metabolism in NSCLC in a p53-independent manner

Although an E3 ligase MDM2 is the major negative regulator of the p53 tumor suppressor, a growing body of evidence suggests its p53-independent oncogenic properties. In particular, MDM2 has been shown to regulate serine metabolism independently of p53 status in several types of neoplasia, including NSCLC. Using the GSEA approach and publicly available molecular data on NSCLC tumors, our bioinformatics data suggest that MDM2 affects a number of metabolic genes, particularly those encoding components of the electron transport chain (ETC). To experimentally elucidate the role of MDM2 in respiration and energy metabolism of NSCLC cell models, we established NSCLC cell lines (WT p53+ A549 and p53-null H1299) overexpressing wild-type MDM2, or its catalytically deficient (C464A) mutant (MUT), or the control vector. Using TMRE staining and SeaHorse energy profiling, we demonstrated that wild-type MDM2, but not its catalytically inactive mutant, significantly increased mitochondrial membrane potential (MMP), glycolysis, respiration, and ATP production in a p53independent manner. Further, we compared MDM2-associated effects of two natural compounds that, according to our docking experiment data, bind MDM2 with affinities similar to nutlin-3A, ganoderic acid A and berberine. Despite the fact that both nutlin-3A and berberine stabilized the MDM2 protein, they displayed differential effects on energy metabolism. Taken together, our data argue that MDM2 affects energy metabolism likely in a p53-independent manner. These results also highlight another pharmacological dimension of using MDM2-targeting compounds as potent inhibitors of glycolysis and respiration in tumor cells.