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TNIK抑制剂KY-05009与受体酪氨酸激酶抑制剂多韦替尼对人多发性骨髓瘤细胞中白细胞介素-6诱导的增殖及Wnt信号通路的协同抑制作用

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.

作者信息

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

机构信息

Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon 34824, Korea.

Present address: Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, College of Medicine, Yonsei University, Seoul 03722, Korea.

出版信息

Oncotarget. 2017 Jun 20;8(25):41091-41101. doi: 10.18632/oncotarget.17056.

DOI:10.18632/oncotarget.17056
PMID:28467797
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5522218/
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.

摘要

多发性骨髓瘤是一种浆细胞恶性肿瘤的致命形式，其特征为浆细胞的异常克隆增殖。特别是，由β-连环蛋白介导的经典Wnt信号通路在多发性骨髓瘤细胞中被激活，刺激其增殖。在此，我们研究了白细胞介素-6诱导的多发性骨髓瘤细胞增殖与Wnt信号通路中肿瘤坏死因子受体相关因子2和Nck相互作用激酶（TNIK）表达之间的关系。白细胞介素-6增加了多发性骨髓瘤细胞的增殖以及TNIK mRNA和蛋白表达。此外，我们检测了TNIK抑制剂KY-05009和受体酪氨酸激酶抑制剂多韦替尼对TNIK的影响，以及抑制TNIK是否能抑制白细胞介素-6诱导的多发性骨髓瘤细胞增殖。KY-05009和多韦替尼通过抑制MM细胞中的Wnt信号通路，协同抑制白细胞介素-6刺激的增殖并诱导细胞凋亡。我们的结果提供了关键信息，即TNIK参与白细胞介素-6依赖的多发性骨髓瘤细胞增殖，抑制涉及TNIK的Wnt信号通路可能是治疗白细胞介素-6依赖的多发性骨髓瘤的一种治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acd0/5522218/0742b9caac3e/oncotarget-08-41091-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acd0/5522218/c19686c33c61/oncotarget-08-41091-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acd0/5522218/ba713988edc9/oncotarget-08-41091-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acd0/5522218/19924d82e676/oncotarget-08-41091-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acd0/5522218/4506f3012d00/oncotarget-08-41091-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acd0/5522218/f67cc2da84d5/oncotarget-08-41091-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acd0/5522218/0742b9caac3e/oncotarget-08-41091-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acd0/5522218/c19686c33c61/oncotarget-08-41091-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acd0/5522218/ba713988edc9/oncotarget-08-41091-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acd0/5522218/19924d82e676/oncotarget-08-41091-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acd0/5522218/4506f3012d00/oncotarget-08-41091-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acd0/5522218/f67cc2da84d5/oncotarget-08-41091-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acd0/5522218/0742b9caac3e/oncotarget-08-41091-g006.jpg

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