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

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Title: Pharmacological Inhibition of MCT4 Reduces 4-Hydroxytamoxifen Sensitivity by Increasing HIF-1 alpha Protein Expression in ER-Positive MCF-7 Breast Cancer Cells
Authors: Nadai, Takanobu Browse this author
Narumi, Katsuya Browse this author →KAKEN DB
Furugen, Ayako Browse this author →KAKEN DB
Saito, Yoshitaka Browse this author →KAKEN DB
Iseki, Ken Browse this author →KAKEN DB
Kobayashi, Masaki Browse this author →KAKEN DB
Keywords: 4-hydroxytamoxifen
monocarboxylate transporter
hypoxia-inducible factor-1 alpha
pharmacological inhibition
breast cancer
Issue Date: 1-Sep-2021
Publisher: The Pharmaceutical Society of Japan (日本薬学会)
Journal Title: Biological & pharmaceutical bulletin
Volume: 44
Issue: 9
Start Page: 1247
End Page: 1253
Publisher DOI: 10.1248/bpb.b21-00030
Abstract: 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.
Type: article
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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