title: 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.
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon, 34824, Korea.
authors.forename: Hae Jung
authors.initials: HJ
authors.lastname: Chon
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon, 34824, Korea.
authors.forename: Yura
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon, 34824, Korea.
authors.forename: Kyoung Jun
authors.initials: KJ
authors.lastname: Bae
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA.
authors.forename: Byung Jin
authors.initials: BJ
authors.lastname: Byun
authors.affiliation: Department of Pharmacology, School of Medicine, Eulji University, Daejeon, 34824, Korea.
authors.forename: Soon Ae
authors.initials: SA
authors.lastname: Kim
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon, 34824, Korea. yeon@eulji.ac.kr.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kim
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000081410:Germinal Center Kinases; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015363:Quinolones / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D000081410:Germinal Center Kinases; D009363:Neoplasm Proteins; D015363:Quinolones; D051176:beta Catenin; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; C000631454:TNIK protein, human
keywords: Apoptosis; Dovitinib; IM-9; Multiple myeloma; TNIK; Wnt signaling