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.