Inactivation of wild-type p53 tumor suppressor by electrophilic prostaglandins

The electrophilic eicosanoids prostaglandins A(1) or A(2) impaired p53-depe ndent transcription of endogenous genes and exogenous p53-luciferase report er plasmids in RKO and HCT 116 colon cancer cells. Cellular accumulation of genetically wild-type, but transcriptionally silent p53 varied as a functi on of exposure time and concentration of prostaglandins A(1) and A(2). Pros taglandins A(1) and A(2) induced a conformational change in wild-type p53 t hat corresponded with its inactivation and its aberrant redistribution from the cytosol to the nucleus. Derangement of its transcriptional activity ma nifested as inhibition of p53-mediated apoptosis by etoposide, a representa tive antineoplastic agent. We conclude that electrophilic eicosanoids impai r 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 carcino ma and adenoma, which often harbor a genetically wild-type, but inactive fo rm of p53 tumor suppressor.