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.