Auraptene is an inhibitor of cholesterol esterification and a modulator of estrogen receptors.
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 IC(50) 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.
de Medina
Philippe
P
Institut National de la Santé et de la Recherche Médicale U-563, Toulouse, France.
Genovese
Salvatore
S
Paillasse
Michael R
MR
Mazaheri
Mahta
M
Caze-Subra
Stephanie
S
Bystricky
Kerstin
K
Curini
Massimo
M
Silvente-Poirot
Sandrine
S
Epifano
Francesco
F
Poirot
Marc
M
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D004965:Estrogen Antagonists / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D066298:In Vitro Techniques; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D009361:Neoplasm Invasiveness; D011869:Radioligand Assay; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic / Q000187:drug effects
D016588:Anticarcinogenic Agents; D003374:Coumarins; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008156:Luciferases; D002785:Sterol O-Acyltransferase; D004851:Epoxide Hydrolases; C019885:cholesterol-5 alpha,6 alpha-epoxide hydrase; C105832:aurapten