Traf2- and Nck-interacting kinase (TNIK) is involved in the anti-cancer mechanism of dovitinib in human multiple myeloma IM-9 cells

Abstract

Traf2- and Nck-interacting kinase (TNIK) is a member of the germinal center kinase family. TNIK was first identified as a kinase that is involved in regulating cytoskeletal organization in many types of cells, and it was recently proposed as a novel therapeutic target in several types of human cancers. Although previous studies suggest that TNIK plays a pivotal role in cancer cell survival and prognosis, its function in hematological cancer cell survival has not been investigated. Here we investigated the relationship between TNIK function and cell viability in multiple myeloma IM-9 cells using TNIK small interfering RNA (siRNA) transfection and dovitinib treatment. Treatment of IM-9 cells with TNIK siRNA and dovitinib treatment reduced cell proliferation. The ATP competing kinase assay and western blot analysis showed that dovitinib strongly inhibited both the interaction of TNIK with ATP (K i, 13 nM) and the activation of Wnt signaling effectors such as β-catenin and TCF4. Dovitinib also induced caspase-dependent apoptosis in IM-9 cells without significant cytotoxicity in PBMCs. Our results provide new evidence that TNIK may be involved in the proliferation of multiple myeloma IM-9 cells and in the anti-cancer activity of dovitinib via inhibition of the endogenous Wnt signaling pathway.

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

“…TNIK is highly expressed in MM cells compared to normal peripheral blood mononuclear cells (PBMCs), and inhibition of TNIK expression by siRNA induces cell death. KY-05009 and dovitinib have a high affinity for the ATP binding site in TNIK and inhibit the protein expression of TNIK and transcriptional activity of Wnt target genes [11, 12]. Through these our recent reports, we confirmed that TNIK can be a potential target for inducing apoptosis activity of KY-05009 and dovitinib in cancer cells.…”

“…In the last 10 years, TNIK has been reported as a novel therapeutic target in several types of cancers. In many studies, the expression of TNIK has been shown to be involved in the survival of human cancer cells, including colorectal, gastric, liver, and hematological cancer [6–11]. Wnt signaling is mediated by TNIK through interactions with β-catenin and following phosphorylation of T-cell factor (TCF) 4 at serine 154 in the nucleus.…”

“…Phosphorylation of TCF4 induces the activation of Wnt target genes, such as CCND1 , AXIN2 , ZCCHC12 , and TCF7 [6]. In addition, the inhibition of TNIK expression by small-interfering RNA (siRNA) suppresses the transcriptional activity of TCF/lymphoid enhancer-binding factor (LEF) and induces apoptosis [7, 11]. A few reports have demonstrated the expression of TNIK and cancer cell proliferation in several types of cancer, but the relevance of TNIK to hematological malignancies, especially MM, has not been sufficiently described [6–11].…”

“…In our previous studies, we investigated the apoptosis-inducing effect of tyrosine kinase inhibitor dovitinib and its inhibition of TNIK kinase activity and endogenous Wnt signaling in human MM cells [11]. TNIK is highly expressed in MM cells compared to normal peripheral blood mononuclear cells (PBMCs), and inhibition of TNIK expression by siRNA induces cell death.…”

“…KY-05009 exerted synergistic anti-proliferative effects with dovitinib and triggered caspase-dependent apoptosis in RPMI8226 cells. We hypothesize that a possible mode of action of KY-05009 and dovitinib is a high affinity for TNIK and subsequent inhibition of kinase activity [11, 12]. This inhibitory effect against TNIK may suppress the proliferation of RPMI8226 cells.…”