TY - JOUR T1 - Auraptene Is an Inhibitor of Cholesterol Esterification and a Modulator of Estrogen Receptors JF - Molecular Pharmacology JO - Mol Pharmacol SP - 827 LP - 836 DO - 10.1124/mol.110.065250 VL - 78 IS - 5 AU - Philippe de Medina AU - Salvatore Genovese AU - Michael R. Paillasse AU - Mahta Mazaheri AU - Stephanie Caze-Subra AU - Kerstin Bystricky AU - Massimo Curini AU - Sandrine Silvente-Poirot AU - Francesco Epifano AU - Marc Poirot Y1 - 2010/11/01 UR - http://molpharm.aspetjournals.org/content/78/5/827.abstract N2 - Auraptene is a prenyloxycoumarin from Citrus species with chemopreventive properties against colitis-related colon and breast cancers through a yet-undefined mechanism. To decipher its mechanism of action, we used a ligand-structure based approach. We established that auraptene fits with a pharmacophore involved in both the inhibition of acyl-CoA:cholesterol acyl transferase (ACAT) and the modulation of estrogen receptors (ERs). We confirmed experimentally that auraptene inhibits ACAT and binds to ERs in a concentration-dependent manner and that it inhibited ACAT in rat liver microsomes and in intact cancer cells of murine and human origins, with an IC50 value in the micromolar range. Auraptene bound to ERs with affinities of 7.8 μM for ERα and 7.9 μM for ERβ, stabilized ERs, and modulated their transcriptional activity via an ER-dependent reporter gene and endogenous genes. We further established that these effects correlated well with the control of growth and invasiveness of tumor cells. Our data shed light on the molecular mechanism underlying the anticancer and chemopreventive effects of auraptene. ER -