Subcellular Localization Relevance and Cancer-Associated Mechanisms of Diacylglycerol Kinases

Abstract

An increasing number of reports suggests a significant involvement of the phosphoinositide (PI) cycle in cancer development and progression. Diacylglycerol kinases (DGKs) are very active in the PI cycle. They are a family of ten members that convert diacylglycerol (DAG) into phosphatidic acid (PA), two-second messengers with versatile cellular functions. Notably, some DGK isoforms, such as DGKα, have been reported to possess promising therapeutic potential in cancer therapy. However, further studies are needed in order to better comprehend their involvement in cancer. In this review, we highlight that DGKs are an essential component of the PI cycle that localize within several subcellular compartments, including the nucleus and plasma membrane, together with their PI substrates and that they are involved in mediating major cancer cell mechanisms such as growth and metastasis. DGKs control cancer cell survival, proliferation, and angiogenesis by regulating Akt/mTOR and MAPK/ERK pathways. In addition, some DGKs control cancer cell migration by regulating the activities of the Rho GTPases Rac1 and RhoA.

Suppressive effects of plumbagin on the growth of human bladder cancer cells via PI3K/AKT/mTOR signaling pathways and EMT

“…Phosphatidylinositol 3-kinase (PI3K) plays many important biological functions in cell proliferation, cell growth, differentiation and apoptosis. Many studies have illustrated that the PI3K signaling pathway could be abnormally activated in multiple types of cancer [ 20 – 22 ]. Various growth factors and signal transduction complexes activate and phosphorylate the receptor tyrosinase to recruit the p85 subunit of PI3K, phosphorylation of phosphatidylinositol is catalyzed and transformed phosphatidyl inositol triphosphate (PIP3).…”

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.…”

Phosphatidic acid inhibits inositol synthesis by inducing nuclear translocation of IP6K1 and repression of myo-inositol-3-P synthase

“…PA is synthesized in multiple subcellular locations, and the acyl chain composition of newly synthesized PA is influenced by the site of synthesis, reflecting differences in the composition of available precursor lipids from which PA is synthesized (Du et al, 2004; Fazio et al, 2020; Zhukovsky et al, 2019). The source of PA is critical for its regulatory functions.…”

“…For example, mono-and di-unsaturated PA species are specifically involved in recruitment and docking of secretory vesicles, whereas poly-unsaturated PA uniquely participates in fusion pore expansion during exocytosis (Tanguy et al, 2021). The site of PA synthesis dictates the specific species of PA produced (Du et al, 2004; Fazio et al, 2020; Zhukovsky et al, 2019). The finding that PA derived from the PM but not from the ER can induce nuclear translocation of IP6K1 (Figure 3) suggests that binding is dependent on the specific PA species synthesized in the PM.…”