Effect of pH on radiation-induced p53 expression

In most tumors, the intratumor environment is acidic. The purpose of this study was to elucidate the effect of acidic extracellular environment on the radiation-induced expression of p53 and related molecular signals. Cultured RKO.C human colorectal cancer cells carrying wild-type p53 were used. Cells grown in pH 7.5 medium or pH 6.6 medium were irradiated with γ-rays, and the expression of p53 and p53 mRNA, as well as the degradation rate of the molecules, was determined. The transcriptional activity for p53 was investigated using cells transfected with a p53 reporter construct. The expression of Mdm2 and the phosphorylation of p53, essential factors for p53 degradation, were also investigated. The pH 6.6 environment prolonged the radiation-induced expression of p53 and p53 mRNA. The radiation-induced increase in transcriptional activity of p53 lasted longer in pH 6.6 medium than in pH 7.5 medium. The degradation of p53 was delayed at pH 6.6. The radiation-induced expression of Mdm2 was markedly suppressed, whereas the phosphorylation of p53 was markedly increased after irradiation in pH 6.6 medium. Acidic environment significantly enhances the radiation-induced expression of p53, partly by increasing the formation of p53 and also partly by slowing down the degradation of p53 through inhibiting p53–Mdm2 complex formation. The potential implication of acidic intratumor microenvironment for the response of tumors to radiotherapy remains to be elucidated.