OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis
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 mu...
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| creator | Wroblewski, David Jiang, Chen Chen Croft, Amanda Farrelly, Margaret L Zhang, Xu Dong Hersey, Peter |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0084073 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0084073</identifier><identifier>PMID: 24367627</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Autophagy - drug effects ; Bcl-2 protein ; Biphenyl Compounds - pharmacology ; Calcium - metabolism ; Cancer therapies ; Cell death ; Cell Line, Tumor ; Cytosol - drug effects ; Cytosol - metabolism ; Drug Resistance, Neoplasm - drug effects ; Endoplasmic reticulum ; Endoplasmic Reticulum Stress - drug effects ; Human behavior ; Humans ; Immunoglobulins ; Leukemia ; Mcl-1 protein ; Medicine ; Melanoma ; Melanoma - pathology ; Myeloid Cell Leukemia Sequence 1 Protein - genetics ; Nitrophenols - pharmacology ; Phagocytosis ; Piperazines - pharmacology ; Protein folding ; Proteins ; Proto-Oncogene Proteins c-bcl-2 - genetics ; Public health ; Pyrroles - pharmacology ; RNA-mediated interference ; Sensitivity ; Signaling ; Sulfonamides - pharmacology ; Unfolded Protein Response - drug effects ; Up-Regulation - drug effects</subject><ispartof>PloS one, 2013-12, Vol.8 (12), p.e84073</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Wroblewski et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Wroblewski et al 2013 Wroblewski et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-fb08d1ceeed2963af0e39121bb4c23079d85f1b949020cc88a62faf40f8c22a83</citedby><cites>FETCH-LOGICAL-c692t-fb08d1ceeed2963af0e39121bb4c23079d85f1b949020cc88a62faf40f8c22a83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868604/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868604/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24367627$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Villunger, Andreas</contributor><creatorcontrib>Wroblewski, David</creatorcontrib><creatorcontrib>Jiang, Chen Chen</creatorcontrib><creatorcontrib>Croft, Amanda</creatorcontrib><creatorcontrib>Farrelly, Margaret L</creatorcontrib><creatorcontrib>Zhang, Xu Dong</creatorcontrib><creatorcontrib>Hersey, Peter</creatorcontrib><title>OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Autophagy - drug effects</subject><subject>Bcl-2 protein</subject><subject>Biphenyl Compounds - pharmacology</subject><subject>Calcium - metabolism</subject><subject>Cancer therapies</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Cytosol - drug effects</subject><subject>Cytosol - metabolism</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum Stress - drug effects</subject><subject>Human behavior</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Leukemia</subject><subject>Mcl-1 protein</subject><subject>Medicine</subject><subject>Melanoma</subject><subject>Melanoma - 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| subjects | Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Autophagy - drug effects Bcl-2 protein Biphenyl Compounds - pharmacology Calcium - metabolism Cancer therapies Cell death Cell Line, Tumor Cytosol - drug effects Cytosol - metabolism Drug Resistance, Neoplasm - drug effects Endoplasmic reticulum Endoplasmic Reticulum Stress - drug effects Human behavior Humans Immunoglobulins Leukemia Mcl-1 protein Medicine Melanoma Melanoma - pathology Myeloid Cell Leukemia Sequence 1 Protein - genetics Nitrophenols - pharmacology Phagocytosis Piperazines - pharmacology Protein folding Proteins Proto-Oncogene Proteins c-bcl-2 - genetics Public health Pyrroles - pharmacology RNA-mediated interference Sensitivity Signaling Sulfonamides - pharmacology Unfolded Protein Response - drug effects Up-Regulation - drug effects |
| title | OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis |
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