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Functional p53 Increases Prostate Cancer Cell Survival After Exposure to Fractionated Doses of Ionizing Radiation¹

Division of Hematology/Oncology, Department of Internal Medicine [S. L. S., P. H. G.] and Department of Radiation Oncology [J. D. E.], University of California, Davis Cancer Center, Sacramento, California 95817

External beam radiation therapy is an effective therapy for localized prostate cancer, although failures occur at high rates. One variable that may affect the radiosensitivity of prostate tumor cells is their p53 status because this gene controls radiation-induced cell cycle arrest, apoptosis, and the repair of DNA damage. Using a system in which p53 function was conditionally restored to p53-null PC3 prostate cancer cells by stable transfection with a human temperature-sensitive p53 mutant allele, we tested the hypothesis that functional p53 increases cell cycle arrest and contributes to increased clonogenic survival after ionizing radiation (IR) of prostate carcinoma cells. Cell cycle arrest and clonogenic survival in response to single and multiple daily exposures to clinically relevant 2-Gy doses of IR were examined. Whereas the temperature-sensitive p53 protein was activated by phosphorylation after IR exposure at both the restrictive and permissive temperatures, Cdkn1/p21 was only induced by functional p53 (at the permissive temperature). In the presence of functional p53, the maintenance of G₂ arrest was significantly longer (P < 0.01), and a small increase in cell survival measured by clonogenic assay was seen after exposure to a single 2-Gy dose of IR. However, functional p53 significantly increased clonogenic survival (P < 0.01) after exposure to daily doses of 2 Gy of IR and contributed to a more sustained G₂ arrest and increased G₁ arrest in response to the multifraction regimen. These studies implicate the presence of wild-type p53 with increased survival of prostate carcinoma cells after fractionated exposure to radiation. Additionally, the data provide evidence that wild-type p53 in prostate tumor cells may reduce the effectiveness of radiation therapy.

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