title: Monomeric and oligomeric flavanols are agonists of membrane androgen receptors.
abstract: The present work reports a new mode of action of the naturally occurring flavanols catechin and epicatechin and their dimers B2 and B5, in the breast cancer T47D cell line, namely, their interaction with membrane androgen receptors. We show that monomeric and dimeric flavanols are complete (B2) or partial displacers of radiolabeled testosterone bound on T47D membranes, with affinities ranging from 1.7 (B5) to 82.2 nM (B2). In addition, they trigger the phosphorylation of the same signaling molecules (FAK, PI3K) as testosterone-BSA, minutes after binding to membrane receptors, leading to actin cytoskeleton polymerization and redistribution, with formation of filopodia and lamellipodia. The PI3K inhibitor wortmannin reverts the effect of polyphenols and testosterone-BSA, providing additional evidence about activation of a similar signaling cascade. Incubation of T47D cells for more than 2 h with polyphenols or testosterone-BSA induces apoptosis, which follows the same time-dependent pattern. We conclude that flavanols (monomers or dimers) are agonists of membrane androgen receptors and could be used as testosterone-protein conjugates for the management of tumors, in which, application of testosterone-BSA induces regression, providing additional data about the mechanism of their antiproliferative action.
authors.affiliation: Laboratory of Experimental Endocrinology, University of Crete School of Medicine, P.O. Box 2208, Heraklion GR-71003, Greece.
authors.forename: Artemissia-Phoebe
authors.initials: AP
authors.lastname: Nifli
authors.forename: Antoine
authors.initials: A
authors.lastname: Bosson-Kouamé
authors.forename: Natalia
authors.initials: N
authors.lastname: Papadopoulou
authors.forename: Christina
authors.initials: C
authors.lastname: Kogia
authors.forename: Marilena
authors.initials: M
authors.lastname: Kampa
authors.forename: Chantal
authors.initials: C
authors.lastname: Castagnino
authors.forename: Christos
authors.initials: C
authors.lastname: Stournaras
authors.forename: Joseph
authors.initials: J
authors.lastname: Vercauteren
authors.forename: Elias
authors.initials: E
authors.lastname: Castanas
mesh_terms: D000199:Actins / Q000187:drug effects; D000728:Androgens; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects / Q000201:enzymology; D005260:Female; D044948:Flavonols / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000819:agonists* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011944:Receptors, Androgen / Q000502:physiology
chemical_list: D000199:Actins; D000728:Androgens; D044948:Flavonols; D008565:Membrane Proteins; D011944:Receptors, Androgen; D019869:Phosphatidylinositol 3-Kinases