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Genes Dev. 2020 Apr 1;34(7-8):544-559. doi: 10.1101/gad.330746.119. Epub 2020 Feb 20.

Estrogen-related receptors are targetable ROS sensors.

Author information

1
Goodman Cancer Research Centre, McGill University, Montréal, Quebec H3A 1A3, Canada.
2
Department of Biochemistry, McGill University, Montréal, Quebec H3G 1Y6, Canada.
3
Department of Medicine, McGill University, Montréal, Quebec H3G 1Y6, Canada.
4
Department of Oncology, McGill University, Montréal, Quebec H3G 1Y6, Canada.

Abstract

Excessive reactive oxygen species (ROS) can cause oxidative stress and consequently cell injury contributing to a wide range of diseases. Addressing the critical gaps in our understanding of the adaptive molecular events downstream ROS provocation holds promise for the identification of druggable metabolic vulnerabilities. Here, we unveil a direct molecular link between the activity of two estrogen-related receptor (ERR) isoforms and the control of glutamine utilization and glutathione antioxidant production. ERRα down-regulation restricts glutamine entry into the TCA cycle, while ERRγ up-regulation promotes glutamine-driven glutathione production. Notably, we identify increased ERRγ expression/activation as a hallmark of oxidative stress triggered by mitochondrial disruption or chemotherapy. Enhanced tumor antioxidant capacity is an underlying feature of human breast cancer (BCa) patients that respond poorly to treatment. We demonstrate that pharmacological inhibition of ERRγ with the selective inverse agonist GSK5182 increases antitumor efficacy of the chemotherapeutic paclitaxel on poor outcome BCa tumor organoids. Our findings thus underscore the ERRs as novel redox sensors and effectors of a ROS defense program and highlight the potential therapeutic advantage of exploiting ERRγ inhibitors for the treatment of BCa and other diseases where oxidative stress plays a central role.

KEYWORDS:

breast cancer; chemotherapy; gene signature; glutamine; glutathione; metabolic flux; mitochondria; nuclear receptor; organoid; oxidative stress; taxane

PMID:
32079653
PMCID:
PMC7111261
[Available on 2020-10-01]
DOI:
10.1101/gad.330746.119

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