2. Academic Validation
  3. GSK-3β/β-catenin pathway plays crucial roles in the regulation of NK cell cytotoxicity against myeloma cells

GSK-3β/β-catenin pathway plays crucial roles in the regulation of NK cell cytotoxicity against myeloma cells

  • FASEB J. 2023 Mar;37(3):e22821. doi: 10.1096/fj.202201658RR.
Jing Ren 1 2,  Xiumei Feng 3,  Yanan Guo 1 2,  Dexiao Kong 1 2,  Yongjing Wang 1 2,  Juan Xiao 1 2,  Wen Jiang 4,  Xiaoli Feng 5,  Xiaoli Liu 1 2,  Ai Li 1 2,  Congcong Sun 1 2,  Mingming He 1 2,  Bingen Li 6,  Juandong Wang 1 2,  Yang Jiang 1 2,  Chengyun Zheng 1 2
Affiliations

Affiliations

  • 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.
PMID: 36794671 DOI: 10.1096/fj.202201658RR
Abstract

The 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.

Keywords

GSK-3β; NF-κB; NK cells; immunotherapy; β-catenin.

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