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

Cancers

Hiromichi Sakai¹  Fumio Sakane²  Masayuki Ebina²  Fumi Hoshino²  Daisuke Takahashi³ 

[1] Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Organization for Research and Academic Information, Shimane University, Izumo 693-8501, Japan;Department of Chemistry, Graduate School of Science, Chiba University, Chiba 263-8522, Japan;Department of Pharmaceutical Health Care and Sciences, Kyushu University, Fukuoka 812-8582, Japan;

关键词: diacylglycerol kinase;    calcium;    tyrosine phosphorylation;    protein kinase C;    nuclear factor-κB;    ERK;   

DOI  :  10.3390/cancers13205190

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown