Pharmacological Inhibition of MCT4 Reduces 4-Hydroxytamoxifen Sensitivity by Increasing HIF-1 alpha Protein Expression in ER-Positive MCF-7 Breast Cancer Cells

Nadai, Takanobu; Narumi, Katsuya; Furugen, Ayako; Saito, Yoshitaka; Iseki, Ken; Kobayashi, Masaki

Pharmacological Inhibition of MCT4 Reduces 4-Hydroxytamoxifen Sensitivity by Increasing HIF-1 alpha Protein Expression in ER-Positive MCF-7 Breast Cancer Cells

Nadai, Takanobu; Narumi, Katsuya; Furugen, Ayako et al.

Biological & pharmaceutical bulletin, 2021, 44(9), 1247-1253

Permalink : https://hdl.handle.net/2115/83022

このアイテムのアクセス数:463件（2026-08-09 14:28 集計）

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https://doi.org/10.1248/bpb.b21-00030			14

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アクセス権	open access
URI	https://hdl.handle.net/2115/83022
タイトル	Pharmacological Inhibition of MCT4 Reduces 4-Hydroxytamoxifen Sensitivity by Increasing HIF-1 alpha Protein Expression in ER-Positive MCF-7 Breast Cancer Cells
著者	Nadai, Takanobu ; Narumi, Katsuya ; Furugen, Ayako ; Saito, Yoshitaka ; Iseki, Ken ; Kobayashi, Masaki
著者名 Nadai, Takanobu
e-Rad_Researcher 90746752 著者名 Narumi, Katsuya
e-Rad_Researcher 90767261 著者名 Furugen, Ayako
e-Rad_Researcher 00835001 著者名 Saito, Yoshitaka
e-Rad_Researcher 40203062 著者名 Iseki, Ken
e-Rad_Researcher 70431319 著者名 Kobayashi, Masaki
言語	英語
キーワード	4-hydroxytamoxifen
	monocarboxylate transporter
	hypoxia-inducible factor-1 alpha
	bindarit
	pharmacological inhibition
	breast cancer
発行日	2021-09-01
出版者	The Pharmaceutical Society of Japan （日本薬学会）
収録物名	Biological & pharmaceutical bulletin
巻(号)	44(9)
ページ	1247-1253
抄録	The rate of glycolysis in cancer cells is higher than that of normal cells owing to high energy demands, which results in the production of excess lactate. Monocarboxylate transporters (MCTs), especially MCT1 and MCT4, play a critical role in maintaining an appropriate pH environment through lactate transport, and their high expression is associated with poor prognosis in breast cancer. Thus, we hypothesized that inhibition of MCTs is a promising therapeutic target for adjuvant breast cancer treatment. We investigated the effect of MCT inhibition in combination with 4-hydroxytamoxifen (4-OHT), an active metabolite of tamoxifen, using two estrogen receptor (ER)-positive breast cancer cell lines, MCF-7 and T47D. Lactate transport was investigated in cellular uptake studies. The cytotoxicity of 4-OHT was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In both cell lines evaluated, MCTI and MCT4 were constitutively expressed at the mRNA and protein levels. (C-14]-L-lactate uptake by both cells was significantly inhibited by bindarit, a selective MCT4 inhibitor, but weakly affected by 5-oxoploline (5-OP), a selective MCT1 inhibitor. The results of the MTT assay showed that combination with bindarit, but not 5-OP, decreased 4-OHT sensitivity. Bindarit significantly increased the levels of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in MCF-7 cells. Moreover, HIF-1 alpha knockdown significantly increased 4-OHT sensitivity, whereas induction of HIF-1 alpha by hypoxia decreased 4-OHT sensitivity in MCF-7 cells. In conclusion, pharmacological MCT4 inhibition confers resistance to 4-OHT rather than sensitivity, by increasing HIF-1 alpha protein levels. In addition, HIF-1 alpha inhibition represents a potential therapeutic strategy for enhancing 4-OHT sensitivity.
資源タイプ	学術雑誌論文
出版タイプ	Version of Record
PISSN	0918-6158
EISSN	1347-5215
関連情報 (isIdenticalTo)	出版社版DOI https://doi.org/10.1248/bpb.b21-00030