Pifithrin-alpha promotes p53-mediated apoptosis in JB6 cells.
Recently, blockage of p53-dependent transcriptional activation and apoptosis by pifithrin-alpha (PFTalpha) 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 PFTalpha 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 PFTalpha itself but were also enhanced by a combination of PFTalpha with UVB or Dox. Furthermore, PFTalpha-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 PFTalpha. Thus, we conclude that PFTalpha is not a specific p53 inhibitor in JB6 cells but is a potential activator of p53-mediated signaling and apoptosis.
Kaji
Akira
A
Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Zhang
Yiguo
Y
Nomura
Masaaki
M
Bode
Ann M
AM
Ma
Wei-Ya
WY
She
Qing-Bai
QB
Dong
Zigang
Z
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D052160:Benzothiazoles; D015153:Blotting, Western; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011233:Precipitin Tests; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects; D012867:Skin / Q000166:cytology / Q000187:drug effects; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D014050:Toluene / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
D000970:Antineoplastic Agents; D052160:Benzothiazoles; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D004317:Doxorubicin; C121565:pifithrin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases