Diacylglycerol kinase α‐selective inhibitors induce apoptosis and reduce viability of melanoma and several other cancer cell lines
Diacylglycerol kinase α‐selective inhibitors induce apoptosis and reduce viability of melanoma and several other cancer cell lines
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二酰甘油激酶 α 选择性抑制剂诱导细胞凋亡并降低黑色素瘤和其他几种癌细胞系的活力
DOI：
10.1002/jcb.28288
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发表时间：
2018
影响因子：
4
通讯作者：
Sakane Fumio
中科院分区：
文献类型：
--
作者：
Yamaki Atsumi;Akiyama Rino;Murakami Chiaki;Takao Saki;Murakami Yuki;Mizuno Satoru;Takahashi Daisuke;Kado Sayaka;Taketomi Akinobu;Shirai Yasuhito;Goto Kaoru;Sakane Fumio
二酰基甘油（DG）激酶（DGK）是磷酸化DG生成磷脂酸（PA）的激酶，由10种同工酶（α-к）组成。最近，我们发现了一种新的小分子抑制剂CU-3，它选择性地抑制α同工酶的活性。此外，我们新获得了化合物A，其选择性地且强烈地抑制I型DGK（α、β和γ）。在本研究中，我们证明了CU-3和化合物A均诱导阿基黑素瘤细胞的凋亡（半胱天冬酶3/7活性和DNA片段化）和活力降低。液相色谱-质谱分析显示，32：0-和34：0-PA物质的产生通常被CU-3和化合物A减弱，表明较低水平的这些PA分子物质参与阿基细胞的凋亡诱导和活力降低。我们确定了DGKα抑制剂对来自难治性癌症的其他几种癌细胞系的影响。除黑色素瘤外，DGKα抑制剂还可增强半胱天冬酶3/7活性，降低肝细胞癌、胶质母细胞瘤和胰腺癌细胞的活力，但对乳腺癌细胞无影响。有趣的是，Western blot分析表明DGKα表达水平与DGK抑制剂的敏感性呈正相关。由于CU-3和化合物A都诱导T细胞产生白细胞介素-2，因此认为这两种化合物可以增强癌症免疫力。综上所述，我们的结果表明DGKα抑制剂是有前途的抗癌药物。
Diacylglycerol (DG) kinase (DGK), which phosphorylates DG to generate phosphatidic acid (PA), consists of ten isozymes (α–к). Recently, we identified a novel small molecule inhibitor, CU‐3, that selectively inhibits the activity of the α isozyme. In addition, we newly obtained Compound A, which selectively and strongly inhibits type I DGKs (α, β, and γ). In the present study, we demonstrated that both CU‐3 and Compound A induced apoptosis (caspase 3/7 activity and DNA fragmentation) and viability reduction of AKI melanoma cells. Liquid chromatography‐mass spectrometry revealed that the production of 32:0‐ and 34:0‐PA species was commonly attenuated by CU‐3 and Compound A, suggesting that lower levels of these PA molecular species are involved in the apoptosis induction and viability reduction of AKI cells. We determined the effects of the DGKα inhibitors on several other cancer cell lines derived from refractory cancers. In addition to melanoma, the DGKα inhibitors enhanced caspase 3/7 activity and reduced the viability of hepatocellular carcinoma, glioblastoma, and pancreatic cancer cells, but not breast adenocarcinoma cells. Interestingly, Western blot analysis indicated that the DGKα expression levels were positively correlated with the sensitivity to the DGK inhibitors. Because both CU‐3 and Compound A induced interleukin‐2 production by T cells, it is believed that these two compounds can enhance cancer immunity. Taken together, our results suggest that DGKα inhibitors are promising anticancer drugs.
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DOI：
10.1073/pnas.90.16.7598
发表时间：
1993-08-15
影响因子：
11.1
作者：
GOTO, K;KONDO, H
通讯作者：
KONDO, H
影响因子：
4.4
作者：
Prinz, Petra U.;Mendler, Anna N.;Noessner, Elfriede
通讯作者：
Noessner, Elfriede
影响因子：
64.8
作者：
SAKANE, F;YAMADA, K;TANABE, T
通讯作者：
TANABE, T
二酰甘油激酶 a 通过 NF-κB 激活抑制肿瘤坏死因子 a 诱导的人黑色素瘤细胞凋亡
DOI：
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发表时间：
2007
期刊：
Biochim.Biophys.Acta-Mol.Cell Biol.Lipids 1771
影响因子：
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作者：
Yanagisawa;K.;et. al.
通讯作者：
et. al.
Sakane F.：“一种新型二酰基甘油激酶同工酶的分子克隆，其具有 pleckstrin 同源结构域和类似于蛋白酪氨酸激酶 EPH 家族的 C 末端尾部”J. Biol。
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