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 24h 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-α genes as well as the p53-regulated Bax gene. The damnacanthal-mediated expression of DR5/TRAIL and TNF-R1/TNF-α 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-α-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-, TNF-α-, and p53-mediated damnacanthal-induced apoptosis require the activation of p38 MAPK and mitochondrion-mediated caspase-dependent pathways.
Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan.
Feng-Lang
FL
Lin
Jue-Liang
JL
Hsu
Chang-Hung
CH
Chou
Wen-Jun
WJ
Wu
Chi-I
CI
Chang
Hung-Jen
HJ
Liu
D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000880:Anthraquinones; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D047888:Receptors, Tumor Necrosis Factor, Type I; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C079170:damnacanthal; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D048051:p38 Mitogen-Activated Protein Kinases; D053181:Caspase 8; D053453:Caspase 9