lnactivation of wild-type p53 tumor suppressor by electrophilic prostaglandins

摘要

The electrophilic eicosanoids prostaglandins A_1 or A_2 impaired p53-dependent transcription of endogenous genes and exogenous p53-luciferase reporter plasmids in RKO and HCT 116 colon cancer cells. Celfular accumulation of genetically wild-type, but transcrip- tionally silent p53 varied as a function of exposure time and concentration of prostaglandins A_1 and A_2. Prostaglandins A1 and A_2 induced a conformational change in wild-type p53 that corre- sponded with its inactivation and its aberrant redistribution from the cytosol to the nucleus. Derangement of its transcriptional activity manifested as inhibition of p53-mediated apoptosis by etoposide, a representative antineoplastic agent. We conclude that electrophilic eicosanoids impair the role of wild-type p53 as a guardian of genomic integrity by a process distinct from somatic mutation or viral oncoprotein binding. This process may pertain to malignant and premalignant conditions, such as colon carcinoma and adenoma, which often harbor a genetically wild-type, but inactive form of p53 tumor suppressor.