Effect of pH on radiation-induced p53 expression.
OBJECTIVE
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.


METHODS
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 gamma-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.


RESULTS
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.


CONCLUSIONS
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.
Choi
Eun Kyung
EK
Department of Therapeutic Radiology, College of Medicine, University of Ulsan, Seoul, Korea.
Roberts
Kenneth P
KP
Griffin
Robert J
RJ
Han
Taehee
T
Park
Heon-Jin
HJ
Song
Chang Won
CW
Park
Heon Joo
HJ
D045744:Cell Line, Tumor / Q000378:metabolism; D003470:Culture Media / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000528:radiation effects
D003470:Culture Media; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53