Abstract
Diacylglycerol kinase (DGK) consists of 10 isozymes. The α-isozyme enhances the proliferation of cancer cells. However, DGKα facilitates the nonresponsive state of immunity known as T-cell anergy; therefore, DGKα enhances malignant traits and suppresses immune surveillance. The aim of this study was to identify a novel small molecule that selectively and potently inhibits DGKα activity. We screened a library containing 9,600 chemical compounds using a newly established high-throughput DGK assay. As a result, we have obtained a promising compound, 5-[(2E)-3-(2-furyl)prop-2-enylidene]-3-[(phenylsulfonyl)amino]2-thioxo-1,3-thiazolidin-4-one) (CU-3), which selectively inhibited DGKα with an IC50 value of 0.6 μM. CU-3 targeted the catalytic region, but not the regulatory region, of DGKα. CU-3 competitively reduced the affinity of DGKα for ATP, but not diacylglycerol or phosphatidylserine. Moreover, this compound induced apoptosis in HepG2 hepatocellular carcinoma and HeLa cervical cancer cells while simultaneously enhancing the interleukin-2 production of Jurkat T cells. Taken together, these results indicate that CU-3 is a selective and potent inhibitor for DGKα and can be an ideal anticancer drug candidate that attenuates cancer cell proliferation and simultaneously enhances immune responses including anticancer immunity.
Highlights
Diacylglycerol kinase (DGK) consists of 10 isozymes
We examined whether CU-3 induces apoptosis in a human hepatocellular carcinoma cell line HepG2
CU-3 was identified as a potent and selective inhibitor against the ␣-isozyme of DGK (Figs. 1 and 2; Table 2)
Summary
Diacylglycerol kinase (DGK) consists of 10 isozymes. The ␣-isozyme enhances the proliferation of cancer cells. DGK␣ facilitates the nonresponsive state of immunity known as T-cell anergy; DGK␣ enhances malignant traits and suppresses immune surveillance. CU-3 competitively reduced the affinity of DGK␣ for ATP, but not diacylglycerol or phosphatidylserine This compound induced apoptosis in HepG2 hepatocellular carcinoma and HeLa cervical cancer cells while simultaneously enhancing the interleukin-2 production of Jurkat T cells. Taken together, these results indicate that CU-3 is a selective and potent inhibitor for DGK␣ and can be an ideal anticancer drug candidate that attenuates cancer cell proliferation and simultaneously enhances immune responses including anticancer immunity.—Liu, K., N. We recently established a simple DGK assay [18] that is useful for constructing an HTS system for detecting DGK inhibitors from chemical compound libraries
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