title: Diacylglycerol kinase inhibitor R59022-induced autophagy and apoptosis in the neuronal cell line NG108-15.
abstract: Phosphatidic acid (PA) is a lipid second messenger and is believed to be involved in cell proliferation and survival. PA is mainly produced by phospholipase D (PLD) and diacylglycerol kinase (DGK). Elevated PLD activity is believed to suppress apoptosis via activation of the mammalian target of rapamycin (mTOR). On the other hand, DGK inhibition has been demonstrated to induce apoptosis, but it is unclear whether DGK can regulate mTOR. Here, we investigated whether DGK inhibition can induce apoptosis and autophagy in neuronal cells, since mTOR is a key mediator of autophagy and the simultaneous activation of apoptosis and autophagy has been detected. A DGK inhibitor, R59022 induced autophagy and apoptosis without serum in NG108-15 cells. Autophagy preceded apoptosis, and apoptosis inhibition did not affect R59022-induced autophagy. R59022-induced autophagy was inhibited by exogenous PA, and protein kinase C activation and increases in intracellular Ca(2+) levels, which are assumed to be caused by diacylglycerol accumulation, did not appear to be involved in R59022-induced autophagy. We also investigated the effects of R59022 on mTOR signaling pathway, and found that the pathway was not inhibited by R59022. These results imply that DGK plays an important role in cell survival via mTOR-independent mechanism.
authors.affiliation: Department of Electrical, Engineering and Bioscience, Center for Advanced Biomedical Sciences, Waseda University (TWIns), 2-2, Wakamatus-cho, Shinjuku-ku, Tokyo 162-8480, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takita
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Konuma
authors.forename: Miki
authors.initials: M
authors.lastname: Hanazato
authors.forename: Hiroko
authors.initials: H
authors.lastname: Inoue
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D019852:Diacylglycerol Kinase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010712:Phosphatidic Acids / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D010712:Phosphatidic Acids; D011744:Pyrimidinones; D013844:Thiazoles; C047505:R 59022; D019852:Diacylglycerol Kinase; D058570:TOR Serine-Threonine Kinases