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

Hassan Choucair; Md Khalilur Rahman; Balasubrahmanyam Umashankar; Yassir Al-Zubaidi; Kirsi Bourget; Yongjuan Chen; Colin Dunstan; Tristan Rawling; Michael Murray

doi:10.1016/j.canlet.2021.11.022

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

Cancer Lett. 2022 Feb 1:526:131-141. doi: 10.1016/j.canlet.2021.11.022. Epub 2021 Nov 22.

Authors

Hassan Choucair¹, Md Khalilur Rahman¹, Balasubrahmanyam Umashankar¹, Yassir Al-Zubaidi¹, Kirsi Bourget¹, Yongjuan Chen², Colin Dunstan³, Tristan Rawling⁴, Michael Murray⁵

Affiliations

¹ Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, New South Wales, 2006, Australia.
² Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, New South Wales, 2006, Australia; Biomaterials and Tissue Engineering Research Unit, School of Biomedical Engineering, University of Sydney, New South Wales, 2006, Australia.
³ Biomaterials and Tissue Engineering Research Unit, School of Biomedical Engineering, University of Sydney, New South Wales, 2006, Australia.
⁴ School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Ultimo, New South Wales, 2007, Australia.
⁵ Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, New South Wales, 2006, Australia. Electronic address: michael.murray@sydney.edu.au.

PMID: 34822928
DOI: 10.1016/j.canlet.2021.11.022

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.

Keywords: Endoplasmic reticulum stress; Mitochondria; Pro-apoptotic agents; Reactive oxygen species; Ureido-fatty acids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Endoplasmic Reticulum Stress / immunology*
Fatty Acids / metabolism*
Female
Humans
Mice
Mitochondria / metabolism*
Reactive Oxygen Species / metabolism*

Substances

Fatty Acids
Reactive Oxygen Species