Structure-based identification of ER and ACAT as molecular targets involved in the chemopreventive activity of the citrus auraptene

Auraptene is a prenyloxycoumarin from Citrus spp. that has been reported to have chemopreventive properties on colitis-related colon cancer. Nevertheless, the molecular mechanisms involved in these effects are still unknown. In these study, we show, using molecular modelling techniques, that auraptene displays three-dimensional structural homology with Sah 58–035 (3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide), a dual inhibitor of Acyl-CoA:cholesterol acyl transferase (ACAT) and estrogen receptor modulator [1]. In vitro experiments confirmed that auraptene inhibits cholesterol esterification in a concentration-dependant manner on tissue extract as well as on intact cells of different origins. Docking studies with the crystal structure of estrogen receptors make auraptene a putative ER-ligand which was confirmed by ER binding experiments. Transcriptional experiments indicate that auraptene behave like a partial ER agonist. Finally we show that auraptene induces growth control on both human colon cell lines and breast cancer cell lines which is consistent with the modulation of these newly identified targets. This work reports the identification of two pharmocological targets of auraptene that account for the chemopreventive and growth control of this geranyloxycoumarin. These datas are useful for a better understanding of the molecular mechanism underlying the observed chemopreventive activity of auraptene. Moreover, our results suggest that auraptene might be beneficial for different pathologies where both targets are involved, such as atherosclerosis, Alzheimer's disease, and cancer.

Acknowledgements: Silvente-Poirot S. is in charge of research at the CNRS. This work was supported by an internal grant from INSERM, the „Conseil Regional Midi-Pyrénnées“ and the „Institut National du Cancer“ through the ResisTH network.

References: 1. De Medina P. et al. (2006)J. Pharm. Exp. Ther. 319: 139–149.