Pifithrin-? alters p53 post-translational modifications pattern and differentially inhibits p53 target genes.

ABSTRACT: Pifithrin-? (PFT-?) is a small molecule which has been widely used as a specific inhibitor of p53 transcription activity. However, its molecular mechanism of action remains unclear. PFT-? has also been described to display potent p53-independent activity in cells. In this study, we addressed the mechanism of action of PFT-?. We found that PFT-? failed to prevent the effects of Mdm2 inhibitor Nutlin-3 on cell cycle and apoptosis in several cancer cell lines. However, PFT-? rescued normal primary fibroblasts from growth inhibition by Nutlin-3. PFT-? displayed a very limited effect on p53-dependent transcription upon its activation by Nutlin-3. Moreover, PFT-? inhibitory effect on transcription was highly dependent on the nature of the p53 target gene. PFT-? attenuated post-translational modifications of p53 without affecting total p53 protein level. Finally, we found that PFT-? can decrease the level of intracellular reactive oxygen species through activation of an aryl hydrocarbon receptor (AHR)-Nrf2 axis in a p53-independent manner. In conclusion, PFT-? inhibits only some aspects of p53 function, therefore it should be used with extreme caution to study p53-dependent processes.

SUBMITTER: Zhu J 

PROVIDER: S-EPMC6978515 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature