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Synergistic inhibition effect of TNIK inhibitor KY-05009 and receptor tyrosine kinase inhibitor dovitinib on IL-6-induced proliferation and Wnt signaling pathway in human multiple myeloma cells

 Yura Lee  ;  Jung-Il Jung  ;  Kyeong-Yong Park  ;  Soon Ae Kim  ;  Jiyeon Kim 
 ONCOTARGET, Vol.8(25) : 41091-41101, 2017-06 
Journal Title
Issue Date
Aniline Compounds / pharmacology* ; Apoptosis / drug effects ; Apoptosis / genetics ; Benzimidazoles / pharmacology* ; Cell Line, Tumor ; Cell Proliferation / drug effects* ; Cell Proliferation / genetics ; Cell Survival / drug effects ; Cell Survival / genetics ; Drug Synergism ; Gene Expression Regulation, Neoplastic / drug effects ; Germinal Center Kinases ; Humans ; Interleukin-6 / pharmacology* ; Multiple Myeloma / genetics ; Multiple Myeloma / metabolism ; Multiple Myeloma / pathology ; Protein Kinase Inhibitors / pharmacology ; Protein Serine-Threonine Kinases / antagonists & inhibitors* ; Protein Serine-Threonine Kinases / genetics ; Protein Serine-Threonine Kinases / metabolism ; Quinolones / pharmacology* ; Thiazoles / pharmacology* ; Wnt Signaling Pathway / drug effects* ; Wnt Signaling Pathway / genetics ; beta Catenin / genetics ; beta Catenin / metabolism
IL-6 ; KY-05009 ; TNIK ; Wnt signaling ; multiple myeloma
Multiple myeloma is a fetal form of plasma cell malignancy characterized by abnormal clonal proliferation of plasma cells. Especially, the canonical Wnt signaling pathway mediated by β-catenin is activated in multiple myeloma cells, stimulating their proliferation. Here, we investigated the relationship between interleukin-6-induced proliferation of multiple myeloma cells and Traf2- and Nck-interacting kinase (TNIK) expression in Wnt signaling. Interleukin-6 increased the proliferation of multiple myeloma cells and TNIK mRNA and protein expression. In addition, we examined the effect on TNIK of TNIK inhibitor KY-05009 and receptor tyrosine kinase inhibitor dovitinib and whether inhibition of TNIK suppresses the interleukin-6-induced proliferation of multiple myeloma cells. KY-05009 and dovitinib synergistically inhibited interleukin-6-stimulated proliferation and induced apoptosis through the inhibition of Wnt signaling in MM cells. Our results provide crucial information that TNIK is involved in the interleukin-6-dependent proliferation of multiple myeloma cells and inhibition of Wnt signaling involving TNIK could be a therapeutic strategy for the treatment of interleukin-6-dependent multiple myeloma.
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