title: Up-Regulation of Transient Receptor Potential Melastatin 6 Channel Expression by Tumor Necrosis Factor-α in the Presence of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor.
abstract: Anti-epidermal growth factor receptor (EGFR) drugs such as erlotinib and gefitinib cause a side effect of hypomagnesemia, but chemotherapy to treat this has not yet been developed. The transient receptor potential melastatin 6 (TRPM6) channel is involved in the reabsorption of Mg2+in the renal tubule. We reported previously that the expression of TRPM6 is up-regulated by epidermal growth factor (EGF) in renal tubular epithelial NRK-52E and HEK293 cells. EGF-induced elevation of TRPM6 expression was inhibited by erlotinib, gefitinib, and lapatinib. We found that tumor necrosis factor-α (TNF-α) increases TRPM6 expression in the presence of erlotinib. Therefore, we investigated what molecules are involved in the up-regulation of TRPM6 expression by TNF-α. EGF increased the levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (p-ERK1/2), which were inhibited by erlotinib. TNF-α did not change p-ERK1/2 levels, but increased the phosphorylation and nuclear localization of nuclear factor-κB (NF-κB), which were blocked by the NF-κB inhibitors BAY 11-7082 and pyrrolidinedithiocarbamate ammonium. Similarly, luciferase reporter activity of human TRPM6 was increased by TNF-α, which was blocked by NF-κB inhibitors, and was inhibited by a mutation in the κB-binding site in the proximal region of the TRPM6 promoter. A chromatin immunoprecipitation assay revealed that NF-κB binds to the κB-binding site, which was blocked by NF-κB inhibitors. In the presence of erlotinib, TNF-α increased Mg2+influx, which was blocked by NF-κB inhibitors. These results suggest that TNF-α reverses the reduction in Mg2+reabsorption caused by anti-EGFR drugs. J. Cell. Physiol. 232: 2841-2850, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Chisa
authors.initials: C
authors.lastname: Furukawa
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Fujii
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Manabe
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.affiliation: Saitama Medical Center, Saitama Medical University, Saitama, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: Department of Pharmacy, Gifu University Hospital, Gifu, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ito
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ikari
mesh_terms: D000818:Animals; D001665:Binding Sites; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000077156:Gefitinib; D057809:HEK293 Cells; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000077341:Lapatinib; D008274:Magnesium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011799:Quinazolines / Q000633:toxicity; D051381:Rats; D065608:Renal Reabsorption / Q000187:drug effects*; D050053:TRPM Cation Channels / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; C507531:TRPM6 protein, rat; D014409:Tumor Necrosis Factor-alpha; D000077341:Lapatinib; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; C483803:Egfr protein, rat; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D008274:Magnesium; D000077156:Gefitinib