Troglitazone is an estrogen-related receptor α and γ inverse agonist

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Graphical abstractTroglitazone functions as an ERRα/γ inverse agonist, suppressing their interactions with PGC-1 coactivators, reducing SOD1/2 expression, and enhancing ROS production to induce p21WAF/GADD45α expression arresting cell cycle.As a ligand for peroxisome proliferators-activated receptor γ (PPARγ), troglitazone inhibits cell growth by mechanisms besides activating PPARγ. In this study, we found that troglitazone interfered with the interactions between estrogen-related receptor α and γ (ERRα and ERRγ) and their coactivator PPARγ coactivator-1α (PGC-1α) functioning as an inverse agonist. Additionally, troglitazone suppressed the expressions of PGC-1α and its related member PGC-1β which are key regulators of mitochondrial function. Consequently, troglitazone reduced mitochondrial mass and suppressed the expressions of superoxide dismutases to elevate reactive oxygen species (ROS) production. The increase in ROS in turn induced the expression of cell cycle inhibitor p21WAF1. We therefore propose that ERRα and ERRγ are alternative targets of troglitazone important for mediating its growth suppressive effect.

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