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Review

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

1
Department of Chemistry, Graduate School of Science, Chiba University, Chiba 263-8522, Japan
2
Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Organization for Research and Academic Information, Shimane University, Izumo 693-8501, Japan
3
Department of Pharmaceutical Health Care and Sciences, Kyushu University, Fukuoka 812-8582, Japan
*
Author to whom correspondence should be addressed.
Academic Editors: Antonia Ávila-Flores and Pedro Torres-Ayuso
Cancers 2021, 13(20), 5190; https://doi.org/10.3390/cancers13205190
Received: 25 September 2021 / Revised: 14 October 2021 / Accepted: 14 October 2021 / Published: 16 October 2021
(This article belongs to the Special Issue Diacylglycerol Kinases in Cancer)
Diacylglycerol (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. View Full-Text
Keywords: diacylglycerol kinase; calcium; tyrosine phosphorylation; protein kinase C; nuclear factor-κB; ERK; mammalian target of rapamycin; Ras-guanyl nucleotide-releasing protein; programmed cell death-1; anticancer immunity diacylglycerol kinase; calcium; tyrosine phosphorylation; protein kinase C; nuclear factor-κB; ERK; mammalian target of rapamycin; Ras-guanyl nucleotide-releasing protein; programmed cell death-1; anticancer immunity
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MDPI and ACS Style

Sakane, F.; Hoshino, F.; Ebina, M.; Sakai, H.; Takahashi, D. The Roles of Diacylglycerol Kinase α in Cancer Cell Proliferation and Apoptosis. Cancers 2021, 13, 5190. https://doi.org/10.3390/cancers13205190

AMA Style

Sakane F, Hoshino F, Ebina M, Sakai H, Takahashi D. The Roles of Diacylglycerol Kinase α in Cancer Cell Proliferation and Apoptosis. Cancers. 2021; 13(20):5190. https://doi.org/10.3390/cancers13205190

Chicago/Turabian Style

Sakane, Fumio, Fumi Hoshino, Masayuki Ebina, Hiromichi Sakai, and Daisuke Takahashi. 2021. "The Roles of Diacylglycerol Kinase α in Cancer Cell Proliferation and Apoptosis" Cancers 13, no. 20: 5190. https://doi.org/10.3390/cancers13205190

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