Development of Novel Cell Lines for High-Throughput Screening to Detect Estrogen-Related Receptor Alpha Modulators

Area of Science:

• Endocrinology and Metabolism
• Molecular Biology
• Cancer Research

Background:

• Estrogen-related receptor alpha (ERRα) is a key regulator of cellular energy metabolism.
• ERRα and its coactivator PGC-1α are vital for energy production and implicated in metabolic disorders and breast cancer.
• Identifying ERRα modulators can elucidate environmental factors contributing to these diseases.

Purpose of the Study:

• To develop high-throughput screening tools for detecting modulators of ERRα signaling.
• To create stable cell lines with intact ERRα pathways, with and without the coactivator PGC-1α.

Main Methods:

• Established HEK293T cell lines expressing an ERRα reporter (ERR) or both reporter and PGC-1α (PGC/ERR).
• Utilized lentiviral constructs for PGC-1α expression and ERRα multiple hormone response element (MHRE) reporters.
• Screened the Library of Pharmacologically Active Compounds (LOPAC) using these cell lines.

Main Results:

• Identified 33 ERR and 22 PGC/ERR agonists, and 54 ERR and 15 PGC/ERR antagonists from the LOPAC library.
• Several potent ERRα agonists, including dietary plant compounds like genistein, were discovered.
• The developed cell lines effectively detected modulators of ERRα signaling.

Conclusions:

• The developed cell lines are effective tools for high-throughput screening.
• These tools can identify environmental chemicals that impact metabolic pathways and breast cancer progression.
• This research aids in understanding the environmental influences on metabolic diseases and cancer.