The aryl-ureido fatty acid CTU activates endoplasmic reticulum stress and PERK/NOXA-mediated apoptosis in tumor cells by a dual mitochondrial-targeting mechanism.

Choucair, H; Rahman, MK; Umashankar, B; Al-Zubaidi, Y; Bourget, K; Chen, Y; Dunstan, C; Rawling, T; Murray, M

The aryl-ureido fatty acid CTU activates endoplasmic reticulum stress and PERK/NOXA-mediated apoptosis in tumor cells by a dual mitochondrial-targeting mechanism.

Choucair, H Rahman, MK Umashankar, B Al-Zubaidi, Y Bourget, K Chen, Y Dunstan, C Rawling, T

Murray, M

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Publisher:: ELSEVIER IRELAND LTD
Publication Type:: Journal Article
Citation:: Cancer Lett, 2022, 526, pp. 131-141
Issue Date:: 2022-02-01

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Field	Value	Language
dc.contributor.author	Choucair, H
dc.contributor.author	Rahman, MK
dc.contributor.author	Umashankar, B
dc.contributor.author	Al-Zubaidi, Y
dc.contributor.author	Bourget, K
dc.contributor.author	Chen, Y
dc.contributor.author	Dunstan, C
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586
dc.contributor.author	Murray, M
dc.date.accessioned	2023-02-08T04:53:20Z
dc.date.available	2021-11-17
dc.date.available	2023-02-08T04:53:20Z
dc.date.issued	2022-02-01
dc.identifier.citation	Cancer Lett, 2022, 526, pp. 131-141
dc.identifier.issn	0304-3835
dc.identifier.issn	1872-7980
dc.identifier.uri	http://hdl.handle.net/10453/166006
dc.description.abstract	The cancer cell mitochondrion is functionally different from that in normal cells and could be targeted to develop novel experimental therapeutics. The aryl-ureido fatty acid CTU (16({[4-chloro-3-(trifluoromethyl)phenyl]-carbamoyl}amino)hexadecanoic acid) is the prototype of a new class of mitochondrion-targeted agents that kill cancer cells. Here we show that CTU rapidly depolarized the inner mitochondrial membrane, selectively inhibited complex III of the electron transport chain and increased reactive oxygen species (ROS) production. From RNA-seq analysis, endoplasmic reticulum (ER)-stress was a major activated pathway in CTU-treated cells and in MDA-MB-231 tumor xenografts from CTU-treated nu/nu mice. Mitochondrion-derived ROS activated the PERK-linked ER-stress pathway and induced the BH3-only protein NOXA leading to outer mitochondrial membrane (OMM) disruption. The lipid peroxyl scavenger α-tocopherol attenuated CTU-dependent ER-stress and apoptosis which confirmed the critical role of ROS. Oleic acid protected against CTU-mediated apoptosis by activating Mcl-1 expression, which increased NOXA sequestration and prevented OMM disruption. Taken together, CTU both uncouples mitochondrial electron transport and activates ROS production which promotes ER-stress-dependent OMM disruption and tumor cell death. Dual-mitochondrial targeting agents like CTU offer a novel approach for development of new anti-cancer therapeutics.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	ELSEVIER IRELAND LTD
dc.relation.ispartof	Cancer Lett
dc.relation.isbasedon	10.1016/j.canlet.2021.11.022
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	Animals
dc.subject.mesh	Apoptosis
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Fatty Acids
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mitochondria
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Animals
dc.subject.mesh	Apoptosis
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Fatty Acids
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mitochondria
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Mitochondria
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Fatty Acids
dc.subject.mesh	Apoptosis
dc.subject.mesh	Female
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Animals
dc.subject.mesh	Apoptosis
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Fatty Acids
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mitochondria
dc.subject.mesh	Reactive Oxygen Species
dc.title	The aryl-ureido fatty acid CTU activates endoplasmic reticulum stress and PERK/NOXA-mediated apoptosis in tumor cells by a dual mitochondrial-targeting mechanism.
dc.type	Journal Article
utslib.citation.volume	526
utslib.location.activity	Ireland
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2023-02-08T04:53:15Z
pubs.publication-status	Published
pubs.volume	526

Abstract:

The cancer cell mitochondrion is functionally different from that in normal cells and could be targeted to develop novel experimental therapeutics. The aryl-ureido fatty acid CTU (16({[4-chloro-3-(trifluoromethyl)phenyl]-carbamoyl}amino)hexadecanoic acid) is the prototype of a new class of mitochondrion-targeted agents that kill cancer cells. Here we show that CTU rapidly depolarized the inner mitochondrial membrane, selectively inhibited complex III of the electron transport chain and increased reactive oxygen species (ROS) production. From RNA-seq analysis, endoplasmic reticulum (ER)-stress was a major activated pathway in CTU-treated cells and in MDA-MB-231 tumor xenografts from CTU-treated nu/nu mice. Mitochondrion-derived ROS activated the PERK-linked ER-stress pathway and induced the BH3-only protein NOXA leading to outer mitochondrial membrane (OMM) disruption. The lipid peroxyl scavenger α-tocopherol attenuated CTU-dependent ER-stress and apoptosis which confirmed the critical role of ROS. Oleic acid protected against CTU-mediated apoptosis by activating Mcl-1 expression, which increased NOXA sequestration and prevented OMM disruption. Taken together, CTU both uncouples mitochondrial electron transport and activates ROS production which promotes ER-stress-dependent OMM disruption and tumor cell death. Dual-mitochondrial targeting agents like CTU offer a novel approach for development of new anti-cancer therapeutics.

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http://hdl.handle.net/10453/166006