Notexin upregulates Fas and FasL protein expression of human neuroblastoma SK-N-SH cells through p38 MAPK/ATF-2 and JNK/c-Jun pathways

Notechis scutatus scutatus notexin induced an increase in Fas and FasL protein expression of human neuroblastoma SK-N-SH cells in a dose- and time-dependent manner. Moreover, notexin treatment upregulated transcription of Fas/FasL mRNA. Downregulation of FADD blocked notexin-induced procaspase-8 degradation and cleavage of Bid and rescued viability of notexin-treated cells. Upon exposure to notexin, activation of JNK and p38 MAPK was observed in SK-N-SH cells. Notexin-induced upregulation of Fas and FasL was suppressed by SB202190 (p38 MAPK inhibitor) and S600125 (JNK inhibitor). Downregulation of p38α MAPK and JNK1 by siRNA proved that upregulation of Fas/FasL was related to p38α MAPK and JNK1 activation. Notexin treatment evoked p38α MAPK-mediated ATF-2 phosphorylation and JNK1-mediated c-Jun phosphorylation. Knockdown of c-Jun and ATF-2 by siRNA or overexpression of dominant-negative c-Jun and ATF-2 revealed that both c-Jun and ATF-2 were crucial for Fas/FasL upregulation. Taken together, our data indicate that notexin-induced upregulation of Fas and FasL is triggered by p38 MAPK/ATF-2 and JNK/c-Jun signaling pathways in SK-N-SH cells.