Diacylglycerol kinase -selective inhibitors induce apoptosis and reduce viability of melanoma and several other cancer cell lines

被引：41

作者：

Yamaki, Atsumi ^{[1
]}

Akiyama, Rino ^{[1
]}

Murakami, Chiaki ^{[1
]}

Takao, Saki ^{[1
]}

Murakami, Yuki ^{[1
]}

Mizuno, Satoru ^{[1
]}

Takahashi, Daisuke ^{[1
]}

Kado, Sayaka ^{[2
]}

Taketomi, Akinobu ^{[3
]}

Shirai, Yasuhito ^{[4
]}

Goto, Kaoru ^{[5
]}

Sakane, Fumio ^{[1
]}

机构：

[1] Chiba Univ, Grad Sch Sci, Dept Chem, Chiba, Japan

[2] Chiba Univ, Ctr Analyt Instrumentat, Chiba, Japan

[3] Hokkaido Univ, Dept Gastroenterol Surg 1, Grad Sch Med, Sapporo, Hokkaido, Japan

[4] Kobe Univ, Grad Sch Agr Sci, Dept Appl Chem Biosci, Fac Agr, Kobe, Hyogo, Japan

[5] Yamagata Univ, Dept Anat & Cell Biol, Sch Med, Yamagata, Japan

来源：

JOURNAL OF CELLULAR BIOCHEMISTRY | 2019年 / 120卷 / 06期

基金：

日本学术振兴会;

关键词：

apoptosis; cancer; diacylglycerol kinase (DGK); inhibitor; melanoma; phosphatidic acid (PA); MOLECULAR-CLONING; ALPHA; EXPRESSION; GAMMA; ACTIVATION; ISOZYME; TARGETS; DOMAIN; RAS;

D O I：

10.1002/jcb.28288

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Diacylglycerol (DG) kinase (DGK), which phosphorylates DG to generate phosphatidic acid (PA), consists of ten isozymes (-k). Recently, we identified a novel small molecule inhibitor, CU-3, that selectively inhibits the activity of the isozyme. In addition, we newly obtained Compound A, which selectively and strongly inhibits type I DGKs (, , and ). 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 DGK inhibitors on several other cancer cell lines derived from refractory cancers. In addition to melanoma, the DGK 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 DGK 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 DGK inhibitors are promising anticancer drugs.

引用

页码：10043 / 10056

页数：14

共 41 条

[1] Activation of diacylglycerol kinase α is required for VEGF-induced angiogenic signaling in vitro [J].