p53 inhibitor pifithrin α can suppress heat shock and glucocorticoid signaling pathways

Pifithrin α (PFTα) is a chemical compound isolated for its ability to suppress p53-mediated transactivation. It can protect cells from p53-mediated apoptosis induced by various stimuli and reduce sensitivity of mice to gamma radiation. Identification of molecular targets of PFTα is likely to provide new insights into mechanisms of regulation of p53 pathway and is important for predicting potential risks associated with administration of PFTα-like p53 inhibitors in vivo. We found that PFTα, in addition to p53, can suppress heat shock and glucocorticoid receptor signaling but has no effect on nuclear factor-κB signaling. PFTα reduces activation of heat shock transcription factor (HSF1) and increases cell sensitivity to heat. Moreover, it reduces activation of glucocorticoid receptor and rescues mouse thymocytes in vitro and in vivo from apoptotic death after dexamethasone treatment. PFTα affected both signaling pathways in a p53-independent manner. These observations suggest that PFTα targets some unknown factor that is common for three major signal transduction pathways.