Recently, blockage of p53-dependent transcriptional activation and apoptosis by pifithrin-α (PFTα) has been reported to be useful for reducing the side effects of cancer therapy and the compound is thus thought to be a specific inhibitor of p53 [Komarov et al., Science 1999;285:1733-1737]. Here, we found that PFTα did not inhibit UVB- or doxorubicin (Dox)-stimulated p53-mediated transcriptional activation and apoptosis in JB6 cells. Instead, p53-dependent activation and apoptosis were not only induced by PFTα itself but were also enhanced by a combination of PFTα with UVB or Dox. Furthermore, PFTα-induced apoptosis was mediated through p53-dependent and -independent signaling pathways. Extracellular signal-regulated kinases and p38 kinase, but not c-jun N-terminal kinases (JNKs), were activated, and these activations were required for phosphorylation and accumulation of p53 in the cellular apoptotic response to PFTα. Thus, we conclude that PFTα is not a specific p53 inhibitor in JB6 cells but is a potential activator of p53-mediated signaling and apoptosis.
- P38 kinase
- Pifithrin-α (PFTα)