High glucose dephosphorylates serine 46 and inhibits p53 apoptotic activity

Background: In response to diverse genotoxic stimuli p53 is activated as transcription factor to exert its tumor-suppressor function. P53 activation requires protein stabilization, nuclear localization and posttranslational modifications in key residues that may influence p53 selection of target genes. Among them, serine 46 (Ser46) phosphorylation is considered specific for apoptotic activation. Hyperglicaemia, the high blood glucose condition, may negatively affect tumor response to therapies through several mechanisms, conferring resistance to drug-induced cell death. However, whether high glucose might modify p53Ser46 phosphorylation has never been addressed. Methods and results: Here, we performed biochemical and molecular analyses in different cancer cell lines treated with chemotherapy in the presence or absence of high glucose condition. Analyses of p53 posttranslational modifications showed that drug-induced p53Ser46 phosphorylation was reduced by high glucose. Such reduction depended by high glucose-induced calyculin A-sensitive phosphatase(s), able to specifically target p53Ser46 phosphorylation. The specific effect on Ser46 phosphorylation was addressed by analysing Ser15 phosphorylation that instead was not modified by high glucose. In agreement, a constitutively phosphorylated Ser46D p53 mutant was resistant to high glucose. As a consequence of phosphoSer46 impairment, high glucose reduced the tumor cell response to drugs, correlating with reduced p53 apoptotic transactivation. The drug-induced apoptotic cell death, reduced by high glucose, was finally restored by the phosphatase inhibitor calyculin A. Conclusions: These data indicate that high glucose specifically inhibited Ser46 phosphorylation thus reducing p53 apoptotic activity. These results uncover a new mechanism of p53 inactivation providing an interesting novel molecular link between metabolic diseases such as diabetes or obesity and tumor progression and resistance to therapies.