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Endocrinology. 2018 Feb 1;159(2):744-753. doi: 10.1210/en.2017-00658.

Identification of Estrogen-Related Receptor α Agonists in the Tox21 Compound Library.

Author information

1
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland.
2
Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, California.
3
Kelly Government Solutions, Durham, North Carolina.
4
Division of the National Toxicology Program, Biomolecular Screening Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.

Abstract

The estrogen-related receptor α (ERRα) is an orphan nuclear receptor (NR) that plays a role in energy homeostasis and controls mitochondrial oxidative respiration. Increased expression of ERRα in certain ovarian, breast, and colon cancers has a negative prognosis, indicating an important role for ERRα in cancer progression. An interaction between ERRα and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) has also recently been shown to regulate an enzyme in the β-oxidation of free fatty acids, thereby suggesting that ERRα plays an important role in obesity and type 2 diabetes. Therefore, it would be prudent to identify compounds that can act as activators of ERRα. In this study, we screened ∼10,000 (8311 unique) compounds, known as the Tox21 10K collection, to identify agonists of ERRα. We performed this screen using two stably transfected HEK 293 cell lines, one with the ERRα-reporter alone and the other with both ERRα-reporter and PGC-1α expression vectors. After the primary screening, we identified more than five agonist clusters based on compound structural similarity analysis (e.g., statins). By examining the activities of the confirmed ERRα modulators in other Tox21 NR assays, eliminating those with promiscuous NR activity, and performing follow-up assays (e.g., small interfering RNA knockdown), we identified compounds that might act as endocrine disrupters through effects on ERRα signaling. To our knowledge, this study is the first comprehensive analysis in discovering potential endocrine disrupters that affect the ERRα signaling pathway.

PMID:
29216352
PMCID:
PMC5774247
DOI:
10.1210/en.2017-00658
[Indexed for MEDLINE]
Free PMC Article

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