Diacylglycerol Kinase α Is a Critical Signaling Node and Novel Therapeutic Target in Glioblastoma and Other Cancers

Dominguez, Charli; Floyd, Desiree H.; Xiao, Aizhen; Mullins, Garrett R.; Kefas, Benjamin; Xin, Wenjun; Yacur, Melissa N.; Abounader, Roger; Lee, Jae K.; Wilson, George P.; Harris, Thurl E.; Purow, Benjamin

doi:10.1158/2159-8290.cd-12-0215

Cited by 95 publications

(131 citation statements)

References 47 publications

(54 reference statements)

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“…It is interesting to investigate the effect of CU-3 on the cell growth of a variety of cancer cells. They also observed that in marked contrast to cancer cells, R59022 did not weaken the growth of noncancerous astrocytes and fibroblasts ( 37 ). In this study, we also observed that although CU-3 enhanced the caspase-3/7 activities of HepG2 hepatocellular carcinoma and HeLa cervical cancer cells ( Fig.…”

Section: Discussionsupporting

confidence: 74%

“…9D ). Therefore, we reproduced their results ( 37 ). These fi ndings suggest that cancer-derived cells and noncancerderived cells may utilize different pathways to induce apoptosis.…”

Section: Discussionsupporting

confidence: 62%

“…10 ). Although it has already been reported that the DGK ␣ inhibitor inhibited cancer cell proliferation ( 37 ), this study provides a new aspect of the DGK ␣ inhibitor, an enhancer of the immune system. Inactivation (anergy induction) of T cells is the main mechanism for advanced tumors to avoid immune action.…”

Section: Discussionmentioning

confidence: 85%

“…signifi cantly inhibited by DGK ␣ -siRNA and R59949, which attenuates DGK ␣ activity ( 18 ). In addition, Dominguez et al ( 37 ) reported that R59022, which most strongly inhibits DGK ␣ ( 18 ), negatively affected the proliferation of glioblastoma, melanoma, breast cancer, and cervical cancer cells. It is interesting to investigate the effect of CU-3 on the cell growth of a variety of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, we utilized HeLa cells (a human cervical carcinoma cell line) because DGK ␣ was highly expressed in the cells ( Fig. 9A ) and a DGK inhibitor R59022 induced their cell death ( 37 ). As shown in Fig.…”

Section: Enhancement Of the Il-2 Production By Cu-3mentioning

confidence: 99%

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A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response

Liu

Kunii

Sakuma

et al. 2016

Journal of Lipid Research

104

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Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to generate phosphatidic acid ( 1-6 ). To date, 10 mammalian DGK isozymes ( ␣ , ␤ , ␥ , ␦ , , , , , , and ) have been identifi ed. These DGK isozymes are divided into fi ve groups (type I-V) according to their structural features ( 1-6 ). Type I DGK isozymes (DGKs ␣ , ␤ , and ␥ ) commonly contain tandem repeats of two EFhand motif domains and are classifi ed as members of the EF-hand family of Ca 2+ binding proteins. In addition to the Ca 2+ binding EF-hand motifs, all type I DGK isozymes contain an N-terminal recoverin homology domain, two cysteine-rich C1 domains, and the C-terminal catalytic region ( 1-6 ).DGK ␣ ( 7, 8 ) is highly expressed in hepatocellular carcinoma and melanoma cells ( 9, 10 ). DGK ␣ expression is involved in hepatocellular carcinoma progression and is a Abstract Diacylglycerol kinase (DGK) consists of 10 isozymes. The ␣ -isozyme enhances the proliferation of cancer cells. However, DGK ␣ facilitates the nonresponsive state of immunity known as T-cell anergy; therefore, DGK ␣ enhances malignant traits and suppresses immune surveillance. The aim of this study was to identify a novel small molecule that selectively and potently inhibits DGK ␣ activity. We screened a library containing 9,600 chemical compounds using a newly established high-throughput DGK assay. Abbreviations: Con A, concanavalin A; CU-3, 5-[(2E)-3-(2-furyl) prop-2-enylidene]-3-[(phenylsulfonyl)amino]2-thioxo-1,3-thiazolidin-4-one; DG, diacylglycerol; DGK, diacylglycerol kinase; HTS, high-through put screening; IL-2, interleukin-2; PA, phosphatidic acid; PS, phosphatidylserine ; R59022, 6-(2-{4-[(4-fluorophenyl)phenylmethylene]1-piperidinyl}ethyl)-7-methyl-5 H -thiazolo-(3,2-a )pyrimidin-5-one; R59949, 3-(2-{4-[bis-(4-fl uorophenyl)methylene]1-piperidinyl}ethyl)-2,3-dihydro-2-thioxo-4(1 H )quinazolinone. This work was supported by Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. This work was also supported by MEXT/JSPS KAKENHI Grant Numbers 22370047 [Grant-in-Aid for Scientifi c Research (B)], 23116505 (Grant-in-Aid for Scientifi c Research on Innovative Areas), 25116704 (Grant-in-Aid for Scientifi c Research on Innovative Areas), 26291017 [Grant-in-Aid for Scientifi c Research (B)], and 15K14470 (Grant

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Section: Discussionsupporting

confidence: 74%

“…9D ). Therefore, we reproduced their results ( 37 ). These fi ndings suggest that cancer-derived cells and noncancerderived cells may utilize different pathways to induce apoptosis.…”

Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Enhancement Of the Il-2 Production By Cu-3mentioning

confidence: 99%

See 3 more Smart Citations

A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response

Liu

Kunii

Sakuma

et al. 2016

Journal of Lipid Research

104

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Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma

Liu,

Wang,

Zhao

et al. 2023

Cancer Communications

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BackgroundIntrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA.MethodsWe performed integrated multiomics analysis in 116 iCCA samples, including whole‐exome sequencing, bulk RNA‐sequencing and proteome analysis. Based on the non‐negative matrix factorization method and the protein abundance of metabolic genes in human genome‐scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5‐ethynyl‐2'‐deoxyuridine (EdU) assay, colony formation assay, RNA‐sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells.ResultsThree metabolic subtypes (S1‐S3) with subtype‐specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune‐suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (KRAS)/AT‐rich interactive domain 1A (ARID1A) mutations. Among the S2 subtype‐specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen‐activated protein kinase (MAPK) signaling.ConclusionVia multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.

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NK-cell dysfunction in human renal carcinoma reveals diacylglycerol kinase as key regulator and target for therapeutic intervention

et al. 2014

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The relevance of NK cells in tumor control is well established in mouse models and human hematologic malignancies; however, their contribution to the control of human solid tumors remains disputed due to problems with in situ detection and reports of functional inactivity in the tumor milieu. In this study, we established a reliable in situ detection method for NK cells. Moreover, we performed analysis to elucidate mechanisms that impair NK-cell function in the tumor milieu and thereby identify therapeutic targets that allow recovery of NK-cell functionality. It was observed that NK cells from clear cell renal cell carcinoma (ccRCC), compared to NK cells from nontumor kidney and peripheral blood lymphocytes (PBLs), displayed conjoint phenotypic alterations and dysfunction induced by the tumor milieu, which were associated mechanistically with high levels of signaling attenuator diacylglycerol kinase (DGK)-a and blunted mitogen-activated protein kinase pathway activation (ERK1/2, Jun kinase). Reinstating NK-cell functionality was possible by DGK inhibition or brief IL-2 culture, interventions that de-repressed the ERK pathway. The extent of alteration and magnitude of recovery could be linked to NK-cell frequency within ccRCC-infiltrating lymphocytes, possibly explaining the observed survival benefit of patients with NK high tumors. In conclusion, DGK-mediated dampening of the ERK pathway ensuing in NK-cell dysfunction was identified as an important escape mechanism in ccRCC. DGK and the ERK pathway thus emerge as promising therapeutic targets to restore suppressed NK-cell activity for the improvement of antitumor immunity.

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Diacylglycerol Kinase α Is a Critical Signaling Node and Novel Therapeutic Target in Glioblastoma and Other Cancers

Cited by 95 publications

References 47 publications

A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response

A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response

Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma

NK-cell dysfunction in human renal carcinoma reveals diacylglycerol kinase as key regulator and target for therapeutic intervention

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