Defective accumulation of p53 protein in X-irradiated human tumor cells with low proteasome activity

Because the loss of p53 function is the most common event in human cancers, p53 gene therapy is now under clinical trial. Here, we examined whether X-irradiation potentiated the function of the exogenous p53 protein induced in H1299 cells and human non-small cell lung carcinoma cells. We found that the induced p53 protein was not accumulated after X-irradiation, although both phosphorylation of the p53 protein at Ser15 and Ser20, and phosphorylation of MDM2 were observed normally. Next, we examined the kinetics of degradation of the p53 protein in the presence of cycloheximide, a translation inhibitor. The level of the p53 protein in HE49 cells decreased rapidly, but there was no change in the H1299 cells. Furthermore, significant accumulation of the p53 protein was observed only in the HE49 cells after being treated for 2 h with ALLN, a proteasome inhibitor. These results indicate that low proteasome activity in H1299 cells cause defective accumulation of the p53 protein. Furthermore, it is possible that proteasome activity in cancer cells may determine the prognosis of the p53 gene therapy.