Activation of p38 MAPK by damnacanthal mediates apoptosis in SKHep 1 cells through the DR5/TRAIL and TNFR1/TNF-α and p53 pathways

The effect of the natural compound damnacanthal from Morinda citrifolia on SKHep 1 cell growth regulation was investigated Treatment of SKHep 1 cells with damnacanthal for 24 h indicated a dose dependent antiproliferative activity Damnacanthal seems to be selective for tumor cell lines since there is only minimal toxicity against normal hepatocyte cells (FL83B) This is first demonstration that damnacanthal mediated apoptosis involves the sustained activation of the p38 MAPK pathway leading to the transcription of the death receptor family genes encoding DR5/TRAIL and TNF R1/TNF-alpha genes as well as the p53-regulated Bax gene The damnacanthal mediated expression of DR5/TRAIL and TNF R1/TNF-alpha results in caspase 8 activation leading to Bid cleavage In turn activated Bid acting with p53-regulated Bax leads to cytochrome c released from mitochondria Into the cytoplasm Combined activation of the death receptors and mitochondrial pathways results in activation of the downstream effecter caspase 3 leading to cleavage of PARP TRAIL- and TNF a-mediated damnacanthal-induced apoptosis could be suppressed by treatment with caspase inhibitors as well as soluble death receptors Fc DR5 and Fc TNF-R1 chimera Taken together this study provided first evidence demonstrating that TRAIL- INF-alpha and p53-mediated damnacanthal-induced apoptosis require the activation of p38 MAPK and mitochondrion mediated caspase-dependent pathways (C) 2010 Elsevier BV All rights reserved