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TRAIL-induced apoptosis of human melanoma cells involves activation of caspase-4.
- Source :
-
Apoptosis : an international journal on programmed cell death [Apoptosis] 2010 Oct; Vol. 15 (10), pp. 1211-22. - Publication Year :
- 2010
-
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.
- Subjects :
- Animals
Blotting, Western
Caspase 3 metabolism
Caspase Inhibitors
Cell Line, Tumor
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Endoplasmic Reticulum metabolism
Endoplasmic Reticulum Chaperone BiP
Enzyme Activation
Gene Expression
Heat-Shock Proteins genetics
Heat-Shock Proteins metabolism
Humans
Mice
RNA Splicing
RNA, Small Interfering
Rabbits
Recombinant Proteins
Regulatory Factor X Transcription Factors
Stress, Physiological
TNF-Related Apoptosis-Inducing Ligand pharmacology
Transcription Factors genetics
Transcription Factors metabolism
Up-Regulation
X-Box Binding Protein 1
Apoptosis
Caspases, Initiator metabolism
Melanoma metabolism
Melanoma pathology
TNF-Related Apoptosis-Inducing Ligand metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1573-675X
- Volume :
- 15
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Apoptosis : an international journal on programmed cell death
- Publication Type :
- Academic Journal
- Accession number :
- 20514521
- Full Text :
- https://doi.org/10.1007/s10495-010-0513-9