PMID- 28049953 OWN - NLM STAT- MEDLINE DCOM- 20170203 LR - 20181202 IS - 1347-5215 (Electronic) IS - 0918-6158 (Linking) VI - 40 IP - 1 DP - 2017 TI - Cobalt Chloride Induces Expression and Function of Breast Cancer Resistance Protein (BCRP/ABCG2) in Human Renal Proximal Tubular Epithelial Cell Line HK-2. PG - 82-87 LID - 10.1248/bpb.b16-00684 [doi] AB - 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-1alpha, 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. FAU - Nishihashi, Katsuki AU - Nishihashi K AD - Laboratory of Pharmaceutics, Osaka University of Pharmaceutical Sciences. FAU - Kawashima, Kei AU - Kawashima K FAU - Nomura, Takami AU - Nomura T FAU - Urakami-Takebayashi, Yumiko AU - Urakami-Takebayashi Y FAU - Miyazaki, Makoto AU - Miyazaki M FAU - Takano, Mikihisa AU - Takano M FAU - Nagai, Junya AU - Nagai J LA - eng PT - Journal Article PL - Japan TA - Biol Pharm Bull JT - Biological & pharmaceutical bulletin JID - 9311984 RN - 0 (ABCG2 protein, human) RN - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2) RN - 0 (Glucose Transporter Type 1) RN - 0 (HIF1A protein, human) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Neoplasm Proteins) RN - 0 (RNA, Messenger) RN - 3G0H8C9362 (Cobalt) RN - BZ114NVM5P (Mitoxantrone) RN - EVS87XF13W (cobaltous chloride) RN - YL5FZ2Y5U1 (Methotrexate) SB - IM MH - ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics/*metabolism MH - Cell Line MH - Cell Survival/drug effects MH - Cobalt/*pharmacology MH - Epithelial Cells/*drug effects/metabolism MH - Glucose Transporter Type 1/genetics MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism MH - Methotrexate/pharmacology MH - Mitoxantrone/pharmacology MH - Neoplasm Proteins/genetics/*metabolism MH - RNA, Messenger/metabolism EDAT- 2017/01/05 06:00 MHDA- 2017/02/06 06:00 CRDT- 2017/01/05 06:00 PHST- 2017/01/05 06:00 [entrez] PHST- 2017/01/05 06:00 [pubmed] PHST- 2017/02/06 06:00 [medline] AID - 10.1248/bpb.b16-00684 [doi] PST - ppublish SO - Biol Pharm Bull. 2017;40(1):82-87. doi: 10.1248/bpb.b16-00684.