The role of the mouse mutant p53R172H in regulating cancer metabolism

The deregulation of cellular metabolic fluxes is frequently observed along with cancer transformation. The observed reprogramming of biochemical pathways in cancer cells is a consequence of the activation of oncogenic signals and inactivation of tumor suppressor genes. Among the latter, the tumor suppressor p53, inactivated in the majority of human cancers, has been demonstrated to exert tumor suppressor functions by directly controlling the metabolic state of the cell. Urea cycle has been shown to be frequently deregulated in multiple cancer types which acquire capacity to recycle ammonia to support tumor biomass and avoid its toxic effects. By a global metabolomic analysis, we show that in mouse pancreatic ductal adenocarcinoma cancer cells, the mutant p53R172H (R175H in human) impacts on urea cycle metabolism. Our data indicate that depletion of p53R172H significantly increases the levels of L-Aspartate, L-Glutamine, Creatine, Phosphocreatine, Creatinine, Proline, Putrescine, Spermidine and Spermine with a direct consequence on energy production pathways and polyamine biosynthesis. Accordingly, we observe that p53R172H-deficient cells display enhanced tolerance to ammonia accumulation, indicating that regulation of urea cycle by this specific p53 mutant variant also impact ammonia detoxification capacity. At the molecular level we find that the expression of the enzymes involved in the urea cycle, Arginase 2 (Arg2) and Creatin Kinase B (CKB), is consistently altered following manipulation of p53R172H, implicating them in this p53 variant regulation of urea cycle. Moreover, the extensive analysis of publicly available ChIP-seq and ATAC-seq data reveals that Arg2 and CkB genomic loci display epigenetic changes during pancreatic tumor progression. Overall, our findings shed light on an unexplored and unexpected tumor suppressive effect of p53R172H and might help to delineate vulnerabilities of therapeutic interest associated to cancer metabolic deregulations.