Affiliation:
1. Department of Hematology The Second Hospital of Shandong University Jinan Shandong China
2. Institute of Biotherapy for Hematological Malignancy Shandong University Jinan Shandong China
3. Department of Hematology The Fourth People's Hospital of Jinan City Jinan Shandong China
4. Institute of Medical Sciences The Second Hospital of Shandong University Jinan Shandong China
5. Department of Clinical Laboratory The Second Hospital of Shandong University Jinan Shandong China
6. R&D Department Weihai Zhengsheng Biotechnology Co., Ltd Weihai China
Abstract
AbstractThe plasma cell malignancy, multiple myeloma (MM), has significantly improved by the application of new drugs and autologous hematopoietic stem cell transplantation. However, MM remains incurable. A number of studies have revealed an anti‐MM effect of natural killer (NK) cells; however, their clinical efficacy is limited. Furthermore, glycogen synthase kinase (GSK)‐3β inhibitors show an antitumor function. In this study, we aimed to evaluate the potential roles of a GSK‐3β inhibitor (TWS119) in the regulation of NK cell cytotoxicity against MM. Our results showed that, in the presence of TWS119, the NK cell line, NK‐92, and in vitro‐expanded primary NK cells exhibited a significantly higher degranulation activity, expression of activating receptors, cellular cytotoxicity, and cytokine secretion when they were exposed to MM cells. Mechanistic studies indicated that TWS119 treatment markedly upregulated RAB27A expression, a key molecule for NK cell degranulation, and induced the colocalization of β‐catenin with NF‐κB in the nucleus of NK cells. More importantly, GSK‐3β inhibition combined with the adoptive transfer of TWS119‐treated NK‐92 cells significantly reduced tumor volume and prolonged the survival time of myeloma‐bearing mice. In summary, our novel findings suggest that targeting GSK‐3β through the activation of β‐catenin/NF‐κB pathway may be an important approach to improve therapeutic efficacy of NK cell transfusion for MM.
Funder
Key Technology Research and Development Program of Shandong
National Natural Science Foundation of China
Subject
Genetics,Molecular Biology,Biochemistry,Biotechnology
Cited by
5 articles.
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