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Attenuated Response of p53 and p21 in Primary Cultures of Human Prostatic Epithelial Cells Exposed to DNA-damaging Agents¹

Department of Radiation Oncology, Institut Gustave-Roussy, Villejuif, France [T. G.], and Department of Radiation Oncology, Division of Radiation Biology [C. K., T. G. G., A. J. G.], and Department of Urology [D. M. P.], Stanford University School of Medicine, Stanford, California 94305-5468

The multifocal origin of prostate cancer suggests a pan-organ defect in a tumor suppressor pathway. Although structural mutations in the p53 gene have been implicated in late-stage prostate cancer, little is known about the p53 response to genotoxic stress in normal human prostatic epithelial cells from which adenocarcinomas originate. We found that the majority (10 of 12) of epithelial cell cultures derived from histologically normal tissues of radical prostatectomy specimens failed to exhibit p53 accumulation in response to ionizing radiation. Epithelial cell cultures derived from benign prostatic hyperplasia and a primary prostatic adenocarcinoma also failed to accumulate p53 in response to ionizing radiation. In contrast, cultures of prostatic stromal cells derived from normal, benign prostatic hyperplasia, or adenocarcinoma tissues exhibited a 3–9-fold induction of p53 within 1–3 h after irradiation. Since p53 regulates a cell cycle checkpoint through the induction 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 G₁-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 functional difference between the DNA damage response of epithelial and stromal prostatic cells and suggest a possible mechanism for the increased susceptibility of prostatic epithelial cells to accumulate genetic alterations.

¹ This work was supported by Grant CA58838-3 from the National Cancer Institute (to A. J. G.) and by Grant DK47551 from the NIH (to D. M. P.). C. K. was partially supported by a Dean's Fellowship.

² Both T. G. and C. K. contributed equally to this work.

³ To whom requests for reprints should be addressed.

Received 6/19/95. Accepted 7/21/95.

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