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

Abstract

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.

Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review)

“…MSAB is a small-molecule compound that binds to β-catenin and promotes proteasomal degradation of β-catenin ( 126 ). KY-05009 ( 128 ), mebendazole ( 129 ) and PF-794 ( 138 ) are TNIK inhibitors that repress phosphorylation of TNIK substrates, such as TCF4, FMNL2, PRICKLE1, SMAD1 and SMAD2, which leads to inhibition of β-catenin-TCF/LEF-dependent transcription and a variety of cellular processes. Among the β-catenin inhibitors mentioned above, BC2059, CWP232228 and ICG-001 repress the expansion of CSCs.…”

Cyclic pentapeptide cRGDfK enhances the inhibitory effect of sunitinib on TGF-β1-induced epithelial-to-mesenchymal transition in human non-small cell lung cancer cells

“…In the last decade, Traf2- and Nck-interacting kinase (TNIK) has been reported as a first-in-class cancer target molecule [ 16 ]. TNIK kinase activity and expression have been shown to be involved in the maintenance of cancer growth in colorectal cancer, blood cancer, and lung adenocarcinoma [ 17 – 20 ]. Notably, we previously reported the potential of TNIK as an anti-cancer target molecule on the TGF-β induced EMT process, migration, and invasion of human lung adenocarcinoma cells [ 18 ].…”

<b><i>ERAP1</i></b> and <b><i>PDE8A</i></b> Are Downregulated in Cattle Protected against Bovine Tuberculosis

“…TNIK is a member of the germinal centre kinase family involved in cell spreading or migration through cytoskeleton organisation [Lee et al 2017]. However, various evidence [Mahmoudi et al, 2009] suggests that TNIK participates in the regulation of the inflammatory response against Salmonella [Liu et al, 2010] and Mycobacterium [Neumann et al, 2010].…”