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,Kyeong-Yong Park,Soon Ae Kim,Jiyeon Kim,Jung-Il Jung

doi:10.18632/oncotarget.17056

Yura Lee, Kyeong-Yong Park + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.17056

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Journal: Oncotarget	Publication Date: Apr 12, 2017
Citations: 17	License type: cc-by

Affiliation: Eulji University, Yonsei University

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.

Highlights

Multiple myeloma (MM) is a plasma cell malignancy characterized by excess clonal proliferation of abnormal plasma cells in the bone marrow, elevated secretion of monoclonal proteins in the serum or urine, and multiple organ damage, including renal failure, hypercalcemia, anemia, and lytic bone resorption [1]
We examined the effect on Traf2- and Nck-interacting kinase (TNIK) of TNIK inhibitor KY-05009 and receptor tyrosine kinase inhibitor dovitinib and whether inhibition of TNIK suppresses the interleukin-6induced proliferation of multiple myeloma 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

Summary

Introduction

Multiple myeloma (MM) is a plasma cell malignancy characterized by excess clonal proliferation of abnormal plasma cells in the bone marrow, elevated secretion of monoclonal proteins in the serum or urine, and multiple organ damage, including renal failure, hypercalcemia, anemia, and lytic bone resorption [1]. MM is estimated to account for approximately 10% of all hematological malignancies but remains an incurable hematological disorder, despite advances in the introduction of new drugs and therapies [2]. New drugs, such as thalidomide, lenalidomide, and bortezomib, have been used for the treatment of relapsed and refractory. 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 [6,7,8,9,10,11]

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