ATTENUATED RESPONSE OF P53 AND P21 IN PRIMARY CULTURES OF HUMAN PROSTATIC EPITHELIAL-CELLS EXPOSED TO DNA-DAMAGING AGENTS

The multifocal origin of prostate cancer suggests a pan-organ defect i n a tumor suppressor pathway. Although structural mutations in the p53 gene have been implicated in late-stage prostate cancer, little is kn own about the p53 response to genotoxic stress in normal human prostat ic epithelial cells from which adenocarcinomas originate. We found tha t the majority (10 of 12) of epithelial cell cultures derived from his tologically normal tissues of radical prostatectomy specimens failed t o exhibit p53 accumulation in response to ionizing radiation. Epitheli al cell cultures derived from benign prostatic hyperplasia and a prima ry prostatic adenocarcinoma also failed to accumulate p53 in response to ionizing radiation. In contrast, cultures of prostatic stromal cell s derived from normal, benign prostatic hyperplasia, or adenocarcinoma tissues exhibited a 3-9-fold induction of p53 within 1-3 h after irra diation. Since p53 regulates a cell cycle checkpoint through the induc tion of the cyclin-cdk inhibitor p21, we examined p21 accumulation and cell cycle arrest following exposure to ionizing radiation. With one exception, epithelial cells that did not display increased p53 or p21 induction did not demonstrate a significant G(1)-S arrest in response to ionizing radiation, whereas stromal cells that accumulated p53 and p21 exhibited a large cell cycle arrest. These results indicate a func tional difference between the DNA damage response of epithelial and st romal prostatic cells and suggest a possible mechanism for the increas ed susceptibility of prostatic epithelial cells to accumulate genetic alterations.