Piceatannol induces Fas and FasL up-regulation in human leukemia U937 cells via Ca2+/p38alpha MAPK-mediated activation of c-Jun and ATF-2 pathways.
To verify whether piceatannol-induced death of leukemia cells was associated with Fas-mediated death pathway, the present study was conducted. Piceatannol-induced apoptotic death of human leukemia U937 cells was characterized by increase in intracellular Ca(2+) concentration ([Ca(2+)]i), ERK inactivation, p38 MPAK activation, degradation of procaspase-8 and production of t-Bid. Piceatannol treatment increased Fas and FasL protein expression, and up-regulated transcription of Fas and FasL mRNA. Down-regulation of FADD blocked piceatannol-induced procaspase-8 degradation and rescued viability of piceatannol-treated cells. Abolition of piceatannol-induced increase in [Ca(2+)]i abrogated p38 MAPK activation and up-regulation of Fas and FasL expression, but restored ERK activation and viability of piceatannol-treated cells. Suppression of p38alpha MAPK or transfection of constitutively active MEK1 abolished piceatannol-induced Fas and FasL up-regulation. Piceatannol treatment repressed ERK-mediated c-Fos phosphorylation but evoked p38alpha MAPK-mediated c-Jun and ATF-2 phosphorylation. Knockdown of c-Fos, c-Jun and ATF-2 by siRNA reflected that c-Fos attenuated the effect of c-Jun and ATF-2 on Fas/FasL up-regulation. Taken together, our data indicate that Fas/FasL up-regulation in piceatannol-treated U937 cells is elicited by Ca(2+)/p38alpha MAPK-mediated activation of c-Jun and ATF-2, and suggest that autocrine Fas-mediated apoptotic mechanism is involved in piceatannol-induced cell death.
Liu
Wen-Hsin
WH
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
Chang
Long-Sen
LS
D051698:Activating Transcription Factor 2 / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D020536:Enzyme Activators / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism*
D051698:Activating Transcription Factor 2; D020536:Enzyme Activators; D053222:Fas Ligand Protein; D016755:Proto-Oncogene Proteins c-jun; D013267:Stilbenes; D019014:fas Receptor; C041525:3,3',4,5'-tetrahydroxystilbene; D002118:Calcium