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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Autores principales:	David Wroblewski, Chen Chen Jiang, Amanda Croft, Margaret L Farrelly, Xu Dong Zhang, Peter Hersey
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/399bc280767548d9a4d02f723a3a9cf9
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spelling	oai:doaj.org-article:399bc280767548d9a4d02f723a3a9cf92021-11-18T08:41:09ZOBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis.1932-620310.1371/journal.pone.0084073https://doaj.org/article/399bc280767548d9a4d02f723a3a9cf92013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24367627/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Anti-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.David WroblewskiChen Chen JiangAmanda CroftMargaret L FarrellyXu Dong ZhangPeter HerseyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e84073 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q David Wroblewski Chen Chen Jiang Amanda Croft Margaret L Farrelly Xu Dong Zhang Peter Hersey OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis.
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.
format	article
author	David Wroblewski Chen Chen Jiang Amanda Croft Margaret L Farrelly Xu Dong Zhang Peter Hersey
author_facet	David Wroblewski Chen Chen Jiang Amanda Croft Margaret L Farrelly Xu Dong Zhang Peter Hersey
author_sort	David Wroblewski
title	OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis.
title_short	OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis.
title_full	OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis.
title_fullStr	OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis.
title_full_unstemmed	OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis.
title_sort	obatoclax and abt-737 induce er stress responses in human melanoma cells that limit induction of apoptosis.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/399bc280767548d9a4d02f723a3a9cf9
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OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis.

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