Abstract
Simple SummaryDiacylglycerol (DG) kinase (DGK) phosphorylates DG to generate phosphatidic acid (PA). DGKα is highly expressed in several refractory cancer cells, including melanoma, hepatocellular carcinoma, and glioblastoma cells, attenuates apoptosis, and promotes proliferation. In cancer cells, PA produced by DGKα plays an important role in proliferation/antiapoptosis. In addition to cancer cells, DGKα is highly abundant in T cells and induces a nonresponsive state (anergy), representing the main mechanism by which advanced cancers avoid immune action. In T cells, DGKα induces 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 activates T cell function. 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.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.
Highlights
Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG, 1,2-diacyl-sn-glycerol) to generate phosphatidic acid (PA, 1,2-diacyl-sn-glycerol-3-phosphate) [1,2,3,4,5]
Miller et al studied the 3D structure of Staphylococcus aureus DGK (DgkB), which is structurally similar to the catalytic domains of mammalian DGKs and its key active site residues [23]
As described above, DGKα consumes different DG molecular species in AKI melanoma cells (16:0/16:0- and 16:0/18:0-PA) [31] and Jurkat T cells (16:0- and/or 16:1-containing DG species) under starved conditions [30]. These results suggest that DG/PA molecular species having different fatty acid moieties in T cells and cancer cells may contribute to distinct functions of DGKα in these cells
Summary
Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG, 1,2-diacyl-sn-glycerol) to generate phosphatidic acid (PA, 1,2-diacyl-sn-glycerol-3-phosphate) [1,2,3,4,5]. Ca2+-dependent detachment of the intramolecular interaction between the EF-hand motifs and the C1 domains is the crucial event that controls DGKα activity and subcellular localization (translocation from the cytosol to membrane fractions). DGKα is a member of type I DGK [1,2,3,4,5] This isozyme contains, from its N terminus, a recoverin homology (RVH) domain [14], two tandem EF-hand motifs, two tandem C1 domains, and a catalytic domain [15] (Figure 1). It is likely that EF-hand motifs in DGKα associate with Ca2+, and the isozyme is activated by Ca2+ only after cell stimulation. Miller et al studied the 3D structure of Staphylococcus aureus DGK (DgkB), which is structurally similar to the catalytic domains of mammalian DGKs and its key active site residues [23]. It is possible that these enzymes utilize the same mechanism and have 3D structures similar to that of DgkB
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