CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：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.
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浆细胞恶性肿瘤多发性骨髓瘤（MM）的治疗因新药和自体造血干细胞移植应用而显著改善，但 MM 仍无法治愈。多项研究已揭示自然杀伤（NK）细胞具有抗 MM 作用，但临床疗效有限。
此外，糖原合酶激酶（GSK）-3 抑制剂具有抗肿瘤功能。本研究旨在评估 GSK-3 抑制剂 TWS119 调节 NK 细胞对 MM 细胞细胞毒性的潜在作用。
结果显示，在 TWS119 存在时，NK-92 细胞系和体外扩增的原代 NK 细胞接触 MM 细胞后，脱颗粒活性、活化受体表达、细胞毒性和细胞因子分泌均显著增强。机制研究表明，TWS119 处理显著上调 NK 细胞脱颗粒关键分子 RAB27A 的表达，并诱导 β-catenin 与 NF-κB 在 NK 细胞核内共定位。更重要的是，GSK-3 抑制联合过继转移 TWS119 处理的 NK-92 细胞，可显著降低骨髓瘤荷瘤小鼠的肿瘤体积并延长生存时间。
总之，我们的新发现提示，通过激活 β-catenin/NF-κB 通路靶向 GSK-3，可能是提高 NK 细胞输注治疗 MM 疗效的重要方法。
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)-3 inhibitors show an antitumor function. In this study, we aimed to evaluate the potential roles of a GSK-3 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 -catenin with NF- B in the nucleus of NK cells.
More importantly, GSK-3 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-3 through the activation of -catenin/NF- B pathway may be an important approach to improve therapeutic efficacy of NK cell transfusion for MM.
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