Effect of intratumor acidity on cell cycle progression after radiation

초록

The interstitial microenvironment in malignant tumors is intrinsically acidic. We have been investigating the radiation-induced apoptosis, clonogenic cell death and G2/M arrest and the pertinent molecular signals in different pH environment in acidic environment. In RKO.C human colorectal cancer cells expressing wild-type p53, the expression of p53 and p21 was significantly increased upon an incubation of the cells in pH 6.6 medium without radiation exposure. When the cells were irradiated and maintained in pH 6.6 medium, the expression of p53 and p21 was delayed but lasted longer in pH 6.6 medium than in pH 7.5 medium. Interestingly, acidic environment caused apoptosis in the cells, but the acidic environment suppressed the radiation-induced apoptosis. The clonogenic cell death after irradiation was less in pH 6.6 medium than in pH 7.5 medium. Cell cycle analysis indicated that the radiation-induced G2/M arrest was markedly prolonged in pH 6.6 medium as compared with that in pH 7.5 medium. The prolongation of radiation-induced G2/M arrest in acidic pH environment appeared to be related to a prolongation of phosphorylation of Cdc2 resulting in a suppression of cyclin B1-Cdc2 kinase activity. Pertinent to above studies, we have investigated the effect of caffeine on the radiation-induced G2/M arrest. Treatment of RKO cells with caffeine prior to irradiation accelerated the decay of radiation-induced G2/M arrest, more so in the acidic environment. It appeared that caffeine suppressed the radiation-induced ATM kinase activity, thereby suppressed Chk2 kinase and p53 activation. Consequently, the radiation-induced G2/M arrest in acidic environment is shortened. It is concluded that the acidic intratumor environment greatly affects the response of tumors to radiotherapy