Metabolic effect of TAp63α: enhanced glycolysis and pentose phosphate pathway, resulting in increased antioxidant defense

TAp63 alpha is a member of the p53 family, which plays a central role in epithelial cancers. Recently, a role has emerged for p53 family members in cancer metabolic modulation. In order to assess whether TAp63 alpha plays a role in cancer metabolism, we exploited p53-null osteosarcoma Tet-On Saos-2 cells, in which the expression of TAp63 alpha was dependent on doxycycline supplementation to the medium. Metabolomics labeling experiments were performed by incubating the cells in C-13-glucose or (CN)-C-13-N-15-glutamine-labeled culture media, as to monitor metabolic fluxes upon induced expression of TAp63 alpha. Induced expression of TAp63 alpha resulted in cell cycle arrest at the G1 phase. From a metabolic standpoint, expression of Tap63 alpha promoted glycolysis and the pentose phosphate pathway, which was uncoupled from nucleotide biosynthesis, albeit prevented oxidative stress in the form of oxidized glutathione. Double C-13-glucose and (CN)-C-13-N-15-glutamine metabolic labeling confirmed that induced expression of TAp63 alpha corresponded to a decreased flux of pyruvate to the Krebs cycle and decreased utilization of glutamine for catabolic purposes in the TCA cycle. Results were not conclusive in relation to anabolic utilization of labeled glutamine, since it is unclear to what extent the observed minor TAp63 alpha-dependent increases of glutamine-derived labeling in palmitate could be tied to increased rates of reductive carboxylation and de novo synthesis of fatty acids. Finally, bioinformatics elaborations highlighted a link between patient survival rates and the co-expression of p63 and rate limiting enzymes of the pentose phosphate pathway, G6PD and PGD.