Cobalt Chloride Induces Expression and Function of Breast Cancer Resistance Protein (BCRP/ABCG2) in Human Renal Proximal Tubular Epithelial Cell Line HK-2

• Published in: Biological & pharmaceutical bulletin Vol. 40; no. 1; pp. 82 - 87
• Main Authors: Nishihashi, Katsuki, Kawashima, Kei, Nomura, Takami, Urakami-Takebayashi, Yumiko, Miyazaki, Makoto, Takano, Mikihisa, Nagai, Junya
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.01.2017; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Accumulation; Activation; Antineoplastic drugs; Antitumor agents; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - genetics; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - metabolism; Binding sites; Breast cancer; breast cancer resistance protein; Cell Line; Cell Survival - drug effects; Chloride; Clear cell-type renal cell carcinoma; Cobalt; Cobalt - pharmacology; Cobalt chloride; Cytotoxicity; Deoxyribonucleic acid; DNA; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Excretion; Fluorescein; Fluorescein isothiocyanate; Gene expression; Glucose transporter; Glucose Transporter Type 1 - genetics; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Kidneys; Methotrexate; Methotrexate - pharmacology; Mitoxantrone; Mitoxantrone - pharmacology; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Regulatory sequences; Renal cell carcinoma; Renal function; renal proximal tubular epithelial cell; RNA, Messenger - metabolism; Substrate inhibition; Substrates
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b16-00684

The human breast cancer resistance protein (BCRP/ABCG2), a member of the ATP-binding cassette transporter family, is a drug transporter restricting absorption and enhancing excretion of many compounds including anticancer drugs. The cis-regulatory elements in the BCRP promoter include a hypoxia response element, i.e., the DNA binding site for hypoxia-inducible factor-1 (HIF-1). In this study, we investigated the effect of cobalt chloride, a chemical inducer of HIF-1α, on the expression and function of BCRP in human renal proximal tubular cell line HK-2. Cobalt chloride treatment significantly increased the mRNA expression of not only glucose transporter 1 (GLUT1), a typical HIF-1 target gene mRNA, but also ABCG2 mRNA in HK-2 cells. The BCRP inhibitor Ko143-sensitive accumulation of BCRP substrates such as Hoechst33342 and mitoxantrone was significantly enhanced by cobalt chloride treatment. In addition, treatment with cobalt chloride significantly increased the Ko143-sensitive accumulation of fluorescein isothiocyanate-labeled methotrexate in HK-2 cells. Furthermore, cobalt chloride treatment attenuated the cytotoxicity induced by mitoxantrone and methotrexate, which might be, at least in part, due to the increase in BCRP-mediated transport activity via HIF-1 activation. These findings indicate that HIF-1 activation protects renal proximal tubular cells against BCRP substrate-induced cytotoxicity by enhancing the expression and function of BCRP in renal proximal tubular cells.