TRAIL-induced apoptosis of human melanoma cells involves activation of caspase-4 |
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Authors: | Zhi Gang Mao Chen Chen Jiang Fan Yang Rick F Thorne Peter Hersey Xu Dong Zhang |
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Institution: | (1) Immunology and Oncology Unit, Newcastle Misericordiae Hospital, Room 443, David Maddison Clinical Sciences Building, Cnr. King and Watt Streets, Newcastle, NSW, 2300, Australia; |
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Abstract: | Although it is conventionally regarded as an inflammatory caspase, recent studies have shown that caspase-4 plays a role in
induction of apoptosis by endoplasmic reticulum (ER) stress. We report here that activation of caspase-4 is also involved
in induction of apoptosis by TNF-related apoptosis-inducing ligand (TRAIL) in human melanoma cells. Treatment with TRAIL resulted
in activation of caspase-4. This appeared to be mediated by caspase-3, in that caspase-4 was activated later than caspase-8,
-9, and -3, and that inhibition of caspase-3 blocked TRAIL-induced caspase-4 activation. Notably, TRAIL triggered ER stress
in melanoma cells as shown by up-regulation of the GRP78 protein and the spliced form of XBP-1 mRNA. This seemed to be necessary
for activation of caspase-4, as activation of caspase-3 by agents that did not trigger ER stress did not cause activation
of caspase-4. Importantly, inhibition of caspase-4 also partially blocked caspase-3 activation, suggesting that activation
of caspase-4 may be positive feed-back mechanism to further enhance caspase-3 activation. Collectively, these results show
that activation of caspase-4 contributes to TRAIL-induced apoptosis and is associated with induction of ER stress by TRAIL
in melanoma cells, and may have important implications for improving therapeutic efficacies of TRAIL in melanoma. |
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