An acidic environment leads to p53 dependent induction of apoptosis in human adenoma and carcinoma cell lines: implications for clonal selection during colorectal carcinogenesis

As tumours are known to acidify their microenvironment and fluctuations in lumenal pH have been reported in a number of colonic disease conditions, we investigated whether lass of p53 function, commonly associated with the ad enoma to carcinoma transition in human colorectal epithelium, was implicate d in the cellular response to changes in extracellular pH, Human colonic ad enoma and carcinoma derived cell lines were incubated at an inital pH range of 5.5-8.0 and the attached cell yield and apoptotic cell yield determined after 4 days. Exposure of all cell lines to an acidic growth environment w as associated with a G1 arrest, down regulation of the retinoblastoma prote in (pRb) protein and snitch to the hypophosphorylated form of the protein, and increased expression of the p21 protein, However, induction of apoptosi s, associated with increased p53 protein expression but not,vith changes in Bcl-2 expression was only detected in the adenoma derived BH/C1 and AA/C1 cell lines which express wild type p53 activity. Furthermore, this inductio n of apoptosis Has inhibited in the transfected cell line AA/273p53/B, in w hich the wild type p53 function has been abrogated. These results suggest t hat acidification of the microenvironment would provide a selective growth advantage for cells that have lost wild type p53 function, leading to clona l expansion of aberrant cell populations.