RRC ID 51973
Author Furukawa C, Fujii N, Manabe A, Matsunaga T, Endo S, Hasegawa H, Ito Y, Yamaguchi M, Yamazaki Y, Ikari A.
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.
Journal J Cell Physiol
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.
Volume 232(10)
Pages 2841-2850
Published 2017-10-1
DOI 10.1002/jcp.25709
PMID 27925186
MeSH Animals Binding Sites Epidermal Growth Factor / pharmacology ErbB Receptors / antagonists & inhibitors* ErbB Receptors / metabolism Erlotinib Hydrochloride / toxicity* Extracellular Signal-Regulated MAP Kinases / metabolism Gefitinib HEK293 Cells Humans Kidney Tubules / drug effects* Kidney Tubules / metabolism Kidney Tubules / physiopathology Lapatinib Magnesium / metabolism* NF-kappa B / metabolism Phosphorylation Promoter Regions, Genetic Protein Binding Protein Kinase Inhibitors / toxicity* Quinazolines / toxicity Rats Renal Reabsorption / drug effects* TRPM Cation Channels / drug effects* TRPM Cation Channels / metabolism Time Factors Transfection Tumor Necrosis Factor-alpha / pharmacology* Up-Regulation
IF 4.522
Times Cited 4
Human and Animal Cells 293(RCB1637)