TY - JOUR
T1 - Estrogen receptor α induction by mitoxantrone increases Abcg2 expression in placental trophoblast cells
AU - Oda, Kenji
AU - Nishimura, Tomohiro
AU - Higuchi, Kei
AU - Ishido, Naomi
AU - Ochi, Kaori
AU - Iizasa, Hisashi
AU - Sai, Yoshimichi
AU - Tomi, Masatoshi
AU - Nakashima, Emi
N1 - Funding Information:
The present study was supported in part by a Grant‐in‐Aid for Scientific Research and a grant for Private Universities matching fund subsidy from the Ministry of Education, Culture, Sports, Science and Technology, Japan, as well as a grant for a Joint Research Project under the Japan–Korea Basic Scientific Cooperation Program of the Japan Society for the Promotion of Science and Korea Science and Engineering Foundation.
PY - 2013/9
Y1 - 2013/9
N2 - 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 10μM mitoxantrone for 24h was increased, compared with that in nontreated cells, whereas 10μM 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.
AB - 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 10μM mitoxantrone for 24h was increased, compared with that in nontreated cells, whereas 10μM 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.
KW - ABC transporter
KW - Cell culture
KW - Disposition
KW - Membrane transporter
KW - Placenta
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U2 - 10.1002/jps.23549
DO - 10.1002/jps.23549
M3 - Article
C2 - 23592396
AN - SCOPUS:84881613659
SN - 0022-3549
VL - 102
SP - 3364
EP - 3372
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 9
ER -
