MDM2 up-regulates the energy metabolism in NSCLC in a p53-independent manner
Elizaveta Fefilova1, Yulia Kirdeeva1, Sergey Parfenyev1
1Institute of Cytology, Russian Academy of Sciences, 194064, St. Petersburg, Russia.
Abstract:
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 p53-independent 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.
Insights
MDM2 regulates cancer cell energy metabolism independently of p53. This protein enhances mitochondrial function and ATP production, offering new therapeutic targets for non-small cell lung cancer (NSCLC).
Area of Science:
- Oncology
- Molecular Biology
- Metabolism
Background:
- MDM2 is a key regulator of the p53 tumor suppressor.
- Emerging evidence indicates MDM2 possesses p53-independent oncogenic functions.
- MDM2 influences serine metabolism in various cancers, including NSCLC, irrespective of p53 status.
Purpose of the Study:
- To investigate the role of MDM2 in cellular respiration and energy metabolism in non-small cell lung cancer (NSCLC) models.
- To explore the p53-independent effects of MDM2 on metabolic pathways.
- To assess the potential of MDM2-targeting compounds as inhibitors of cancer cell metabolism.
Main Methods:
- Bioinformatic analysis using Gene Set Enrichment Analysis (GSEA) on public NSCLC molecular data.
- Establishment of NSCLC cell lines (A549 and H1299) overexpressing wild-type or catalytically inactive MDM2.
- Experimental validation using TMRE staining and Seahorse energy profiling to measure mitochondrial membrane potential, glycolysis, respiration, and ATP production.
- In silico docking experiments and in vitro assessment of natural compounds (ganoderic acid A, berberine) targeting MDM2.
Main Results:
- Bioinformatic analysis suggested MDM2 impacts metabolic genes, particularly those in the electron transport chain (ETC).
- Wild-type MDM2 significantly increased mitochondrial membrane potential, glycolysis, respiration, and ATP production in NSCLC cells, independent of p53.
- The catalytically inactive MDM2 mutant did not exhibit these metabolic effects.
- Natural compounds ganoderic acid A and berberine showed potential for MDM2 binding, with differential impacts on energy metabolism despite stabilizing MDM2.
Conclusions:
- MDM2 promotes energy metabolism in NSCLC cells through p53-independent mechanisms, likely by enhancing mitochondrial function.
- These findings reveal a novel oncogenic role for MDM2 in regulating cellular respiration.
- MDM2-targeting compounds represent a promising therapeutic strategy for inhibiting cancer cell glycolysis and respiration.
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