Diacylglycerol Kinases in Cancer

Dear Colleagues, 

Diacylglycerol kinases (DGK) are a conserved family of enzymes that transform the lipid diacylglycerol (DAG) into phosphatidic acid (PA). DGK are distinctive enzymes because they constitute a node in which lipid signaling and metabolism convey, and then integrate to generate efficient cell outputs. The DGK lipid substrate and product have essential functions. They are important constituents of membranes and critical intermediators of the phosphatidyl inositol (PtdIns) cycle. They also promote the membrane recruitment and subsequent activation of several key proteins, including protein kinase C (PKC), Ras activator proteins, Raf, mammalian target of rapamycin (mTOR), integrins, and tyrosine kinases. The binding of DAG or PA to their target proteins initiates different signaling cascades that dictate how cells grow, differentiate, and migrate. For this reason, DGK activity must be exquisitely controlled to guarantee cell homeostasis. 

In mammals, there are ten different DGK isoforms that vary in the presence of regulatory domains that confer each DGK specificity to control discrete pools of DAG and PA. In recent years, our understanding of the complex and different functions exerted by DGK have highlighted their potential to develop new anticancer therapies. DGK can act as either suppressors or positive regulators of cell transformation and cancer progression, and alterations in their expression and activity have been linked to specific cancer types. DGKa isoform is the most studied DGK and constitutes a clear example of the multifaceted roles of these enzymes. DGKa inhibition has no effect in normal cells but severely disrupts tumor growth since cancer cells become addicted to this kinase. Moreover, DGKa has an opposite function in the lymphocytes that infiltrate the tumors, in which it attenuates their anticancer properties. Thus, DGKa inhibitors could be highly effective in impairing tumor growth by acting at several levels. In addition to DGKa, another DGK isoform can offer similar therapeutic opportunities, as is the case for DGKz. This isoform also inhibits T lymphocytes and controls cancer cell metabolism. As tumors progress, they develop new strategies to adapt and resist the adverse conditions they encounter, and many of these new strategies rely on the connection between their lipid metabolism and the signaling pathways necessary to survive. This Special Issue of Cancers aims to highlight the exciting field of DGK biology to envisage new prospects for cancer therapeutic modalities.

Dr. Antonia Ávila-Flores
Dr. Pedro Torres-Ayuso
Guest Editor

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