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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antineoplastic Agents / pharmacology*
-
Apoptosis / drug effects*
-
Autophagy / drug effects
-
Biphenyl Compounds / pharmacology*
-
Calcium / metabolism
-
Cell Line, Tumor
-
Cytosol / drug effects
-
Cytosol / metabolism
-
Drug Resistance, Neoplasm / drug effects
-
Endoplasmic Reticulum Stress / drug effects*
-
Humans
-
Indoles
-
Melanoma / pathology*
-
Myeloid Cell Leukemia Sequence 1 Protein / genetics
-
Nitrophenols / pharmacology*
-
Piperazines / pharmacology
-
Proto-Oncogene Proteins c-bcl-2 / genetics
-
Pyrroles / pharmacology*
-
Sulfonamides / pharmacology*
-
Unfolded Protein Response / drug effects
-
Up-Regulation / drug effects
Substances
-
ABT-737
-
Antineoplastic Agents
-
Biphenyl Compounds
-
Indoles
-
MCL1 protein, human
-
Myeloid Cell Leukemia Sequence 1 Protein
-
Nitrophenols
-
Piperazines
-
Proto-Oncogene Proteins c-bcl-2
-
Pyrroles
-
Sulfonamides
-
obatoclax
-
Calcium
Grants and funding
This work was supported by grants from the National Health & Medical Research Council (
www.nhmrc.gov.au) and the Hunter Melanoma Foundation (
http://hmf.org.au). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.