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OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis.
- Source :
-
PloS one [PLoS One] 2013 Dec 19; Vol. 8 (12), pp. e84073. Date of Electronic Publication: 2013 Dec 19 (Print Publication: 2013). - Publication Year :
- 2013
-
Abstract
- Anti-apoptotic Bcl-2 family proteins, in particular, Mcl-1, are known to play a critical role in resistance of human melanoma cells to induction of apoptosis by endoplasmic reticulum stress and other agents. The present study examined whether the BH3 mimetics, Obatoclax and ABT-737, which inhibit multiple anti-apoptotic Bcl-2 family proteins, would overcome resistance to apoptosis. We report that both agents induced a strong unfolded protein response (UPR) and that RNAi knockdown of UPR signalling proteins ATF6, IRE1α and XBP-1 inhibited Mcl-1 upregulation and increased sensitivity to the agents. These results demonstrate that inhibition of anti-apoptotic Bcl-2 proteins by Obatoclax and ABT-737 appears to elicit a protective feedback response in melanoma cells, by upregulation of Mcl-1 via induction of the UPR. We also report that Obatoclax, but not ABT-737, strongly induces autophagy, which appears to play a role in determining melanoma sensitivity to the agents.
- Subjects :
- Autophagy drug effects
Calcium metabolism
Cell Line, Tumor
Cytosol drug effects
Cytosol metabolism
Drug Resistance, Neoplasm drug effects
Humans
Indoles
Myeloid Cell Leukemia Sequence 1 Protein genetics
Piperazines pharmacology
Proto-Oncogene Proteins c-bcl-2 genetics
Unfolded Protein Response drug effects
Up-Regulation drug effects
Antineoplastic Agents pharmacology
Apoptosis drug effects
Biphenyl Compounds pharmacology
Endoplasmic Reticulum Stress drug effects
Melanoma pathology
Nitrophenols pharmacology
Pyrroles pharmacology
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24367627
- Full Text :
- https://doi.org/10.1371/journal.pone.0084073