GSK-3β/β-catenin Pathway Played Curial Roles in the Regulation of NK Cell Cytotoxicity against Myeloma Cells

Abstract

Abstract The plasma cell malignancy multiple myeloma (MM) has been improved significantly by new drugs application and autologous hemopoietic stem transplantation. However, MM remains incurable. A number of studies have revealed an anti-MM effect of Nature killer (NK) cells, but their clinical efficacy was rather limited. Glycogen synthase kinase (GSK)-3β has been shown to have an antitumor function. To evaluate potential roles of GSK-3β inhibitor (TWS119) in the regulation of NK cell cytotoxicity against MM, we analyzed killing effect of NK cells on MM cells. Our results showed that in the presence of TWS119, 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 colocalization of β-catenin with NF-κB in the nucleus of NK cells. More importantly, adoptive transfer of NK-92 cells significantly prolonged survival time of myeloma-bearing mice. In summary, our current novel findings suggest that targeting on GSK-3β through activation of β-catenin/NF-κB pathway maybe an important approach to improve therapeutic efficacy of NK cells transfusion for MM.