二酰基甘油激酶α在癌细胞增殖和凋亡中的作用。,Cancers

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二酰基甘油激酶α在癌细胞增殖和凋亡中的作用。
Cancers ( IF 4.5 ) Pub Date : 2021-10-16 , DOI: 10.3390/cancers13205190
Fumio Sakane ₁ , Fumi Hoshino ₁ , Masayuki Ebina ₁ , Hiromichi Sakai ₂ , Daisuke Takahashi ₃

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二酰基甘油 (DG) 激酶 (DGK) 磷酸化 DG 以生成磷脂酸 (PA)。α 同工酶被 Ca2+ 通过其 EF-hand 基序和酪氨酸磷酸化激活。DGKα 在多种难治性癌细胞中高度表达，包括黑色素瘤、肝细胞癌和胶质母细胞瘤细胞。在黑色素瘤细胞中，DGKα 是一种抗凋亡因子，可通过非典型蛋白激酶 C (PKC) ζ 介导的 NF-κB 磷酸化激活核因子-κB (NF-κB)。DGKα 通过 Raf-MEK-ERK 途径作为增殖活性的增强剂，从而加剧肝细胞癌的进展。在胶质母细胞瘤和黑色素瘤细胞中，DGKα 通过增强雷帕霉素途径的磷酸二酯酶 (PDE)-4A1-哺乳动物靶点来减弱细胞凋亡。当 PA 激活 PKCζ、Raf 和 PDE 时，DGKα 产生的 PA 可能在癌细胞的增殖/抗凋亡中起重要作用。除癌细胞外，DGKα 在 T 细胞中高度丰富并诱导无反应状态（无反应），这是晚期癌症逃避免疫作用的主要机制。在 T 细胞中，DGKα 减弱 Ras-鸟苷酸释放蛋白的活性，该蛋白被 DG 激活并通过消耗 DG 避免无反应性。因此，DGKα 特异性抑制剂有望成为一种双重有效的抗癌治疗方法，可抑制癌细胞增殖并同时增强 T 细胞功能。此外，DGKα 的抑制协同增强了程序性细胞死亡 1/程序性细胞死亡配体 1 阻断的抗癌作用。综合起来，

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The Roles of Diacylglycerol Kinase α in Cancer Cell Proliferation and Apoptosis.

Diacylglycerol (DG) kinase (DGK) phosphorylates DG to generate phosphatidic acid (PA). The α isozyme is activated by Ca2+ through its EF-hand motifs and tyrosine phosphorylation. DGKα is highly expressed in several refractory cancer cells including melanoma, hepatocellular carcinoma, and glioblastoma cells. In melanoma cells, DGKα is an antiapoptotic factor that activates nuclear factor-κB (NF-κB) through the atypical protein kinase C (PKC) ζ-mediated phosphorylation of NF-κB. DGKα acts as an enhancer of proliferative activity through the Raf-MEK-ERK pathway and consequently exacerbates hepatocellular carcinoma progression. In glioblastoma and melanoma cells, DGKα attenuates apoptosis by enhancing the phosphodiesterase (PDE)-4A1-mammalian target of the rapamycin pathway. As PA activates PKCζ, Raf, and PDE, it is likely that PA generated by DGKα plays an important role in the proliferation/antiapoptosis of cancer cells. In addition to cancer cells, DGKα is highly abundant in T cells and induces a nonresponsive state (anergy), which represents the main mechanism by which advanced cancers escape immune action. In T cells, DGKα attenuates the activity of Ras-guanyl nucleotide-releasing protein, which is activated by DG and avoids anergy through DG consumption. Therefore, a DGKα-specific inhibitor is expected to be a dual effective anticancer treatment that inhibits cancer cell proliferation and simultaneously enhances T cell functions. Moreover, the inhibition of DGKα synergistically enhances the anticancer effects of programmed cell death-1/programmed cell death ligand 1 blockade. Taken together, DGKα inhibition provides a promising new treatment strategy for refractory cancers.

更新日期：2021-10-16

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