The roles of diacylglycerol kinase α in cancer cell proliferation and apoptosis

Fumio Sakane, Fumi Hoshino, Masayuki Ebina, Hiromichi Sakai, Daisuke Takahashi

Research output: Contribution to journalReview articlepeer-review

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number5190
JournalCancers
Volume13
Issue number20
DOIs
Publication statusPublished - Oct 1 2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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