title: Estrogen receptor α induction by mitoxantrone increases Abcg2 expression in placental trophoblast cells.
abstract: Substrate-induced upregulation of ATP-binding cassette subfamily G member 2 (ABCG2) has been well studied in cancer cells, but it is also important to understand whether ABCG2 is upregulated by its substrates in tissues in which it is constitutively expressed. In the present study, we aimed to clarify the regulatory mechanism of Abcg2 expression by its substrate, mitoxantrone, in placental cells. Abcg2 mRNA expression in rat placental TR-TBT 18d-1 cells treated with 10 μM mitoxantrone for 24 h was increased, compared with that in nontreated cells, whereas 10 μM pheophorbide-a had no effect. Methylated CpG level in the promoter region of the Abcg2 gene was low and was not altered by mitoxantrone. On the contrary, mitoxantrone markedly increased the expression of estrogen receptor (ER) α and progesterone receptor (PR) B. Fulvestrant, an ER antagonist, attenuated the mitoxantrone-induced increase of Abcg2 mRNA expression, whereas mifepristone, a PR antagonist, had little effect. 17β-estradiol, an ER ligand, positively regulated the mitoxantrone-induced increase of Abcg2 expression. DNA demethylation by 5-aza-2-deoxycytidine treatment increased ERα expression, but mitoxantrone failed to facilitate the demethylation of ERα promoter in TR-TBT 18d-1 cells. In conclusion, Abcg2 expression is induced by mitoxantrone via the induction of ERα in TR-TBT 18d-1 cells.
authors.affiliation: Keio University, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Oda
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishimura
authors.forename: Kei
authors.initials: K
authors.lastname: Higuchi
authors.forename: Naomi
authors.initials: N
authors.lastname: Ishido
authors.forename: Kaori
authors.initials: K
authors.lastname: Ochi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Iizasa
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Sai
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tomi
authors.forename: Emi
authors.initials: E
authors.lastname: Nakashima
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002734:Chlorophyll / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008942:Mitoxantrone / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D002734:Chlorophyll; D008942:Mitoxantrone; C032623:pheophorbide a
keywords: ABC transporter; cell culture; disposition; membrane transporter; placenta