P53 Mutants G245S and R337H Associated with the Li-Fraumeni Syndrome Regulate Distinct Metabolic Pathways

Li-Fraumeni and Li-Fraumeni-like syndromes (LFS/LFL) are hereditary cancer predisposition disorders associated with germline mutations in the TP53 tumor suppressor gene. Here, we stably expressed LFS/LFL-associated p53 mutants R337H and G245S in p53-null H1299 cells to study their cellular and molecular effects. Mutant proteins showed distinct oligomerization states and opposing effects on cell proliferation and viability. Stable expression of p53 enhanced cell proliferation and spheroid formation, while cells stably expressing p53 showed reduced proliferation and clonogenicity, along with increased cell death. Mass spectrometry analysis revealed that proteins whose expression was induced by p53 or p53 expression were related to distinct metabolic profiles. Proteins upregulated by p53 expression were associated with a Warburg phenotype, while proteins upregulated by p53 expression were related to oxidative phosphorylation and fatty acid oxidation. Differences in mitochondrial mass and activity between cells stably expressing p53 or p53 were further corroborated by High Resolution Respirometry, flow cytometry and qPCR assays. The implications of the different oncogenic properties of p53 and p53 on the clinical manifestation and treatment of LFS/LFL patients carrying these mutations are discussed.