STAT1, STAT3 and p38MAPK are involved in the apoptotic effect induced by a chimeric cyclic interferon-alpha2b peptide.
In the search of mimetic peptides of the interferon-alpha2b molecule (IFN-alpha2b), we have previously designed and synthesized a chimeric cyclic peptide of the IFN-alpha2b that inhibits WISH cell proliferation by inducing an apoptotic response. Here, we first studied the ability of this peptide to activate intracellular signaling pathways and then evaluated the participation of some signals in the induction of apoptosis. Stimulation of WISH cells with the cyclic peptide showed tyrosine phosphorylation of Jak1 and Tyk2 kinases, tyrosine and serine phosphorylation of STAT1 and STAT3 transcription factors and activation of p38 MAPK pathway, although phosphorylation levels or kinetics were in some conditions different to those obtained under IFN-alpha2b stimulus. JNK and p44/42 pathways were not activated by the peptide in WISH cells. We also showed that STAT1 and STAT3 downregulation by RNA interference decreased the antiproliferative activity and the amount of apoptotic cells induced by the peptide. Pharmacological inhibition of p38 MAPK also reduced the peptide growth inhibitory activity and the apoptotic effect. Thus, we demonstrated that the cyclic peptide regulates WISH cell proliferation through the activation of Jak/STAT signaling pathway. In addition, our results indicate that p38 MAPK may also be involved in cell growth regulation. This study suggests that STAT1, STAT3 and p38 MAPK would be mediating the antitumor and apoptotic response triggered by the cyclic peptide in WISH cells.
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Viviana C
VC
Institute of Biochemistry and Biophysics (UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956-C1113AAD Buenos Aires, Argentina.
Peña
Clara
C
Roguin
Leonor P
LP
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000235:genetics / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; D048051:p38 Mitogen-Activated Protein Kinases