Combined inhibition/silencing of diacylglycerol kinase α and ζ simultaneously and synergistically enhances interleukin‐2 production in T cells and induces cell death of melanoma cells,Journal of Cellular Biochemistry

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Combined inhibition/silencing of diacylglycerol kinase α and ζ simultaneously and synergistically enhances interleukin‐2 production in T cells and induces cell death of melanoma cells
Journal of Cellular Biochemistry ( IF 3.0 ) Pub Date : 2021-01-05 , DOI: 10.1002/jcb.29876
Saki Takao ₁ , Rino Akiyama ₁ , Fumio Sakane ₁

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The α‐isozyme of diacylglycerol kinase (DGK) enhances cancer cell proliferation and, conversely, it promotes the nonresponsive immune state known as T‐cell anergy. Moreover, a DGKα‐selective inhibitor, CU‐3, induced cell death in cancer‐derived cells and simultaneously enhanced T‐cell interleukin‐2 production. In addition to DGKα, DGKζ is also known to induce T‐cell anergy. In the present study, we examined whether combined inhibition/silencing of DGKα and DGKζ synergistically enhanced T‐cell activity. Combined treatment with CU‐3 or DGKα‐small interfering RNA (siRNA) and DGKζ‐siRNA more potently enhanced T‐cell receptor‐crosslink‐dependent interleukin‐2 production in Jurkat T cells than treatment with either alone. Intriguingly, in addition to activating T cells, dual inhibition/silencing of DGKα and DGKζ synergistically reduced viability and increased caspase 3/7 activity in AKI melanoma cells. Taken together, these results indicate that combined inhibition/silencing of DGKα and DGKζ simultaneously and synergistically enhances interleukin‐2 production in T cells and induces cell death in melanoma. Therefore, dual inhibition/silencing of these DGK isozymes represents an ideal therapy that potently attenuates cancer cell proliferation and simultaneously enhances immune responses that impact anticancer immunity.

中文翻译：

联合抑制/沉默二酰基甘油激酶 α 和 ζ 同时协同增强 T 细胞中白细胞介素 2 的产生并诱导黑色素瘤细胞的细胞死亡

二酰基甘油激酶 (DGK) 的 α-同工酶增强癌细胞增殖，相反，它促进无反应性免疫状态，称为 T 细胞无反应性。此外，DGKα 选择性抑制剂 CU-3 可诱导癌细胞死亡，同时增强 T 细胞白细胞介素 2 的产生。除了 DGKα，已知 DGKζ 还可以诱导 T 细胞无反应性。在本研究中，我们检查了 DGKα 和 DGKζ 的联合抑制/沉默是否协同增强了 T 细胞活性。CU-3 或 DGKα-小干扰 RNA (siRNA) 和 DGKζ-siRNA 的联合治疗比单独治疗更有效地增强了 Jurkat T 细胞中 T 细胞受体交联依赖性白细胞介素-2 的产生。有趣的是，除了激活 T 细胞，DGKα 和 DGKζ 的双重抑制/沉默协同降低了 AKI 黑色素瘤细胞的活力并增加了半胱天冬酶 3/7 活性。综上所述，这些结果表明 DGKα 和 DGKζ 的联合抑制/沉默同时和协同增强 T 细胞中白细胞介素-2 的产生并诱导黑色素瘤中的细胞死亡。因此，这些 DGK 同工酶的双重抑制/沉默代表了一种理想的治疗方法，可有效减弱癌细胞增殖，同时增强影响抗癌免疫的免疫反应。

更新日期：2021-01-05

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