title: Δ(9)-Tetrahydrocannabinol disrupts estrogen-signaling through up-regulation of estrogen receptor β (ERβ).
abstract: Δ(9)-Tetrahydrocannabinol (Δ(9)-THC) has been reported as possessing antiestrogenic activity, although the mechanisms underlying these effects are poorly delineated. In this study, we used the estrogen receptor α (ERα)-positive human breast cancer cell line, MCF-7, as an experimental model and showed that Δ(9)-THC exposures markedly suppresses 17β-estradiol (E2)- induced MCF-7 cell proliferation. We demonstrate that these effects result from Δ(9)-THC's ability to inhibit E2-liganded ERα activation. Mechanistically, the data obtained from biochemical analyses revealed that (i) Δ(9)-THC up-regulates ERβ, a repressor of ERα, inhibiting the expression of E2/ERα-regulated genes that promote cell growth and that (ii) Δ(9)-THC induction of ERβ modulates E2/ERα signaling in the absence of direct interaction with the E2 ligand binding site. Therefore, the data presented support the concept that Δ(9)-THC's antiestrogenic activities are mediated by the ERβ disruption of E2/ERα signaling.
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy , 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Shuso
authors.initials: S
authors.lastname: Takeda
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Yoshida
authors.forename: Hajime
authors.initials: H
authors.lastname: Nishimura
authors.forename: Mari
authors.initials: M
authors.lastname: Harada
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Okajima
authors.forename: Hiroko
authors.initials: H
authors.lastname: Miyoshi
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Amamoto
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Watanabe
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Omiecinski
authors.forename: Hironori
authors.initials: H
authors.lastname: Aramaki
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000737:chemistry / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000096:biosynthesis / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D008024:Ligands; D013759:Dronabinol