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

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)-3ß inhibitors show an antitumor function. In this study, we aimed to evaluate the potential roles of a GSK-3ß 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 ß-catenin with NF-κB in the nucleus of NK cells. More importantly, GSK-3ß 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-3ß through the activation of ß-catenin/NF-κB pathway may be an important approach to improve therapeutic efficacy of NK cell transfusion for MM.