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

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.

A Drosophila in vivo chemical screen reveals that combination drug treatment targeting MEK and DGKα mitigates Ras-driven polarity-impaired tumourigenesis

“…Our findings raise many questions that remain to be investigated, such as whether DGKα activity is elevated in Ras-driven polarity-impaired cells and, if so, how this occurs, and whether increased PA-signalling or decreased DAG signalling provide the critical function of DGKα in tumourigenesis. However, since DGKα is upregulated and oncogenic in human cancer (Chen et al, 2019;Fazio et al, 2020;Merida et al, 2017;Sakane et al, 2021), the findings from our study suggest that Rasdriven polarity-impaired cancers may be particularly addicted to DGKα for tumour survival, and suggests that DGKα-inhibitors combined with Ras pathway inhibitors will be a highly effective drug combination for anti-cancer therapy in these cancers. DGKα inhibitors have been considered for development as anti-cancer therapy not only for their effect on the cancer but also on the T-cell anti-cancer immune response (Arranz-Nicolas and Merida, 2020;Sakane et al, 2008;Sakane et al, 2016).…”

“…DGK α is considered an oncogene, being upregulated in many cancers, and promotes cell proliferation and cell survival (Chen et al, 2019; Fazio et al, 2020; Merida et al, 2017; Sakane et al, 2021). Mechanistically, we showed that inhibition of DGK α in human mammary epithelial cells harbouring the H-RAS oncogene and knockdown of the cell polarity gene, SCRIB , resulted in reduced MEK and mTOR activity.…”

“…Whether other pathways known to be regulated by DGK α (Sakane et al, 2021) are important targets in SCRIB RNAi /H-RAS G12V cells will be important to investigate. One such pathway, activated by PA, is atypical protein kinase C zeta (PKC ζ ) – Nuclear factor kappa B (NF κ B) signalling, which promotes cell survival (Kai et al, 2009; Sakane et al, 2021).…”

“…Whether other pathways known to be regulated by DGK α (Sakane et al, 2021) are important targets in SCRIB RNAi /H-RAS G12V cells will be important to investigate. One such pathway, activated by PA, is atypical protein kinase C zeta (PKC ζ ) – Nuclear factor kappa B (NF κ B) signalling, which promotes cell survival (Kai et al, 2009; Sakane et al, 2021). Atypical protein kinase C (aPKC), is also a cell polarity regulator that plays important roles in establishing and maintaining apical-basal cell polarity of epithelial cells (Tepass, 2012; Vorhagen and Niessen, 2014), and also negatively regulates the Hippo negative tissue growth control signalling pathway in both mammalian cells (Archibald et al, 2015) and Drosophila (Doggett et al, 2011; Grzeschik et al, 2010).…”

The Role of Diacylglycerol Kinase in the Amelioration of Diabetic Nephropathy

“…Further, a human trial observed protection against podocyte apoptosis by green tea polyphenols in DN [ 89 ]. In cancer cells, it is well known that DGKα prevents apoptosis via various signaling pathways, followed by PA production [ 104 , 105 , 106 ], suggesting the involvement of DGKα in the prevention of apoptosis of podocytes by green tea polyphenols, especially EGCG. Taken together, DGKα activation ameliorates DN by not only inhibiting PKCs by reducing the amount of DG but also by generating PA activating downstream signaling pathways.…”