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Cancers
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Diacylglycerol Kinases in Cancer
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Diacylglycerol Kinases in Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (1 February 2023) | Viewed by 13577

Special Issue Editors

Dr. Antonia Ávila-Flores

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Guest Editor
Department of Immunology and Oncology (DIO), Centro Nacional de Biotecnologia (CNB), CSIC, Madrid, Spain
Interests: lipid signaling; diacylglycerol; phosphatidic acid; lipid kinases; cancer immunotherapy; cancer metabolism; cancer drug resistance
Dr. Pedro Torres-Ayuso

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Guest Editor
Signaling Networks in Cancer Section,Laboratory of Cell and Developmental Signaling, National Cancer Institute, Frederick, MD 21702, USA
Interests: cancer biology; precision medicine; functional genomics; signal transduction; protein kinases; lipid kinases; squamous cell carcinomas

Special Issue Information

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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • diacylglycerol
  • phosphatidic acid
  • lipid kinases
  • lipid metabolism
  • drug resistance
  • cancer therapy
  • immunotherapy
  • melanoma
  • colon cancer
  • src kinase
  • mTOR
  • tumor-infiltrating lymphocyte
  • R59949
  • ritanserin
  • melanoma
  • glioblastoma
  • breast cancer
  • ALK

Published Papers (4 papers)

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Research

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26 pages, 5104 KiB  
Article
Epigenetic Modulation of Radiation-Induced Diacylglycerol Kinase Alpha Expression Prevents Pro-Fibrotic Fibroblast Response
by Chun-Shan Liu, Reka Toth, Ali Bakr, Ashish Goyal, Md Saiful Islam, Kersten Breuer, Anand Mayakonda, Yu-Yu Lin, Peter Stepper, Tomasz P. Jurkowski, Marlon R. Veldwijk, Elena Sperk, Carsten Herskind, Pavlo Lutsik, Dieter Weichenhan, Christoph Plass, Peter Schmezer and Odilia Popanda
Cancers 2021, 13(10), 2455; https://doi.org/10.3390/cancers13102455 - 18 May 2021
Cited by 8 | Viewed by 3257
Abstract
Radiotherapy, a common component in cancer treatment, can induce adverse effects including fibrosis in co-irradiated tissues. We previously showed that differential DNA methylation at an enhancer of diacylglycerol kinase alpha (DGKA) in normal dermal fibroblasts is associated with radiation-induced fibrosis. After [...] Read more.
Radiotherapy, a common component in cancer treatment, can induce adverse effects including fibrosis in co-irradiated tissues. We previously showed that differential DNA methylation at an enhancer of diacylglycerol kinase alpha (DGKA) in normal dermal fibroblasts is associated with radiation-induced fibrosis. After irradiation, the transcription factor EGR1 is induced and binds to the hypomethylated enhancer, leading to increased DGKA and pro-fibrotic marker expression. We now modulated this DGKA induction by targeted epigenomic and genomic editing of the DGKA enhancer and administering epigenetic drugs. Targeted DNA demethylation of the DGKA enhancer in HEK293T cells resulted in enrichment of enhancer-related histone activation marks and radiation-induced DGKA expression. Mutations of the EGR1-binding motifs decreased radiation-induced DGKA expression in BJ fibroblasts and caused dysregulation of multiple fibrosis-related pathways. EZH2 inhibitors (GSK126, EPZ6438) did not change radiation-induced DGKA increase. Bromodomain inhibitors (CBP30, JQ1) suppressed radiation-induced DGKA and pro-fibrotic marker expression. Similar drug effects were observed in donor-derived fibroblasts with low DNA methylation. Overall, epigenomic manipulation of DGKA expression may offer novel options for a personalized treatment to prevent or attenuate radiotherapy-induced fibrosis. Full article
(This article belongs to the Special Issue Diacylglycerol Kinases in Cancer)
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Review

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22 pages, 2481 KiB  
Review
DGKα, Bridging Membrane Shape Changes with Specific Molecular Species of DAG/PA: Implications in Cancer and Immunosurveillance
by José Carlos Bozelli, Jr. and Richard M. Epand
Cancers 2022, 14(21), 5259; https://doi.org/10.3390/cancers14215259 - 26 Oct 2022
Cited by 4 | Viewed by 1728
Abstract
Cancer immunotherapy has revolutionized the oncology field. Despite the success, new molecular targets are needed to increase the percentage of patients that benefits from this therapy. Diacylglycerol kinase α (DGKα) has gathered great attention as a potential molecular target in immunotherapy because of [...] Read more.
Cancer immunotherapy has revolutionized the oncology field. Despite the success, new molecular targets are needed to increase the percentage of patients that benefits from this therapy. Diacylglycerol kinase α (DGKα) has gathered great attention as a potential molecular target in immunotherapy because of its role in cancer proliferation and immunosuppression. DGKα catalyzes the ATP-dependent phosphorylation of diacylglycerol (DAG) to produce phosphatidic acid (PA). Since both lipids are potent signaling messengers, DGKα acts as a switch between different signaling pathways. Its role in cancer and immunosuppression has long been ascribed to the regulation of DAG/PA levels. However, this paradigm has been challenged with the identification of DGKα substrate acyl chain specificity, which suggests its role in signaling could be specific to DAG/PA molecular species. In several biological processes where DGKα plays a role, large membrane morphological changes take place. DGKα substrate specificity depends on the shape of the membrane that the enzyme binds to. Hence, DGKα can act as a bridge between large membrane morphological changes and the regulation of specific molecular species of DAG/PA. Bearing in mind the potential therapeutic benefits of targeting DGKα, here, the role of DGKα in cancer and T cell biology with a focus on the modulation of its enzymatic properties by membrane shape is reviewed. The goal is to contribute to a global understanding of the molecular mechanisms governing DGKα biology. This will pave the way for future experimentation and, consequently, the design of better, more potent therapeutic strategies aiming at improving the health outcomes of cancer patients. Full article
(This article belongs to the Special Issue Diacylglycerol Kinases in Cancer)
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10 pages, 464 KiB  
Review
Delivering Glioblastoma a Kick—DGKα Inhibition as a Promising Therapeutic Strategy for GBM
by Benjamin Purow
Cancers 2022, 14(5), 1269; https://doi.org/10.3390/cancers14051269 - 01 Mar 2022
Cited by 1 | Viewed by 3050
Abstract
Diacylglycerol kinase α (DGKα) inhibition may be particularly relevant for the treatment of glioblastoma (GBM), a relatively common brain malignancy incurable with current therapies. Prior reports have shown that DGKα inhibition has multiple direct activities against GBM cells, including suppressing the oncogenic pathways [...] Read more.
Diacylglycerol kinase α (DGKα) inhibition may be particularly relevant for the treatment of glioblastoma (GBM), a relatively common brain malignancy incurable with current therapies. Prior reports have shown that DGKα inhibition has multiple direct activities against GBM cells, including suppressing the oncogenic pathways mTOR and HIF-1α. It also inhibits pathways associated with the normally treatment-resistant mesenchymal phenotype, yielding preferential activity against mesenchymal GBM; this suggests possible utility in combining DGKα inhibition with radiation and other therapies for which the mesenchymal phenotype promotes resistance. The potential for DGKα inhibition to block or reverse T cell anergy also suggests the potential of DGKα inhibition to boost immunotherapy against GBM, which is generally considered an immunologically “cold” tumor. A recent report indicates that DGKα deficiency increases responsiveness of macrophages, indicating that DGKα inhibition could also have the potential to boost macrophage and microglia activity against GBM—which could be a particularly promising approach given the heavy infiltration of these cells in GBM. DGKα inhibition may therefore offer a promising multi-pronged attack on GBM, with multiple direct anti-GBM activities and also the ability to boost both adaptive and innate immune responses against GBM. However, both the direct and indirect benefits of DGKα inhibition for GBM will likely require combinations with other therapies to achieve meaningful efficacy. Furthermore, GBM offers other challenges for the application of DGKα inhibitors, including decreased accessibility from the blood-brain barrier (BBB). The ideal DGKα inhibitor for GBM will combine potency, specificity, and BBB penetrability. No existing inhibitor is known to meet all these criteria, but the strong potential of DGKα inhibition against this lethal brain cancer should help drive development and testing of agents to bring this promising strategy to the clinic for patients with GBM. Full article
(This article belongs to the Special Issue Diacylglycerol Kinases in Cancer)
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13 pages, 1266 KiB  
Review
The Roles of Diacylglycerol Kinase α in Cancer Cell Proliferation and Apoptosis
by Fumio Sakane, Fumi Hoshino, Masayuki Ebina, Hiromichi Sakai and Daisuke Takahashi
Cancers 2021, 13(20), 5190; https://doi.org/10.3390/cancers13205190 - 16 Oct 2021
Cited by 12 | Viewed by 4520
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Diacylglycerol Kinases in Cancer)
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