Anti-proliferative effects of tricyclodecan-9-yl-xanthogenate (D609) involve ceramide and cell cycle inhibition.
Anti-proliferative effects of tricyclodecan-9-yl-xanthogenate (D609) involve ceramide and cell cycle inhibition.
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DOI：
10.1007/s12035-012-8254-0
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发表时间：
2012-06
影响因子：
5.1
通讯作者：
Dempsey, Robert J.
中科院分区：
文献类型：
--
作者：
Gusain, Anchal;Hatcher, James F.;Adibhatla, Rao Muralikrishna;Wesley, Umadevi V.;Dempsey, Robert J.
三环癸烷-9-基-黄原酸酯（D 609）抑制磷脂酰胆碱（PC）-磷脂酶C（PLC）和/或鞘磷脂（SM）合酶（SMS）。抑制SMS可以增加神经酰胺水平，这可以抑制细胞增殖。在这里，我们研究了D 609如何改变个体炎症和神经胶质细胞增殖。用100 μM D 609处理显著减弱RAW 264.7巨噬细胞、N9和BV-2小胶质细胞以及DITNC 1星形胶质细胞的增殖，而不影响细胞活力。D 609显著抑制BV-2小胶质细胞BrdU掺入，并导致G1期细胞积聚，S期细胞数量减少。D 609处理2小时显着增加BV-2小胶质细胞中的神经酰胺水平，在培养基改变后，22小时后恢复到对照水平。这表明D 609的作用可能至少部分通过SMS抑制增加神经酰胺来介导。蛋白质印迹法表明，2小时的BV-2小胶质细胞与D 609治疗增加细胞周期蛋白依赖性激酶（Cdk）抑制剂p21的表达和下调磷酸化视网膜母细胞瘤（Rb），这两个恢复到基础水平后22小时去除D 609。外源性C8-神经酰胺也抑制BV-2小胶质细胞增殖而不丧失活力，并减少BrdU掺入，支持神经酰胺参与D 609介导的细胞周期阻滞。我们目前的数据表明，D 609可能在中风后提供益处（Adibhatla和Hatcher 2010. Mol Neurobiol 41：206-217）通过神经酰胺介导的细胞周期停滞，从而限制神经胶质细胞增殖。
Tricyclodecan-9-yl-xanthogenate (D609) inhibits phosphatidylcholine (PC)-phospholipase C (PLC) and/or sphingomyelin (SM) synthase (SMS). Inhibiting SMS can increase ceramide levels, which can inhibit cell proliferation. Here we examined how individual inflammatory and glia cell proliferation is altered by D609. Treatment with 100 μM D609 significantly attenuated the proliferation of RAW 264.7 macrophages, N9 and BV-2 microglia, and DITNC1 astrocytes, without affecting cell viability. D609 significantly inhibited BrdU incorporation in BV-2 microglia and caused accumulation of cells in G1 phase with decreased number of cells in the S phase. D609 treatment for 2 h significantly increased ceramide levels in BV-2 microglia, which following a media change, returned to control levels 22 h later. This suggests that the effect of D609 may be mediated, at least in part, through ceramide increase via SMS inhibition. Western blots demonstrated that 2 h treatment of BV-2 microglia with D609 increased expression of the cyclin-dependent kinase (Cdk) inhibitor p21 and down-regulated phospho-retinoblastoma (Rb), both of which returned to basal levels 22 h after removal of D609. Exogenous C8-ceramide also inhibited BV-2 microglia proliferation without loss of viability and decreased BrdU incorporation, supporting the involvement of ceramide in D609-mediated cell cycle arrest. Our current data suggest that D609 may offer benefit after stroke (Adibhatla and Hatcher 2010. Mol Neurobiol 41:206-217) through ceramide-mediated cell cycle arrest, thus restricting glial cell proliferation.
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影响因子：
4.4
作者：
Adibhatla, Rao Muralikrishna;Hatcher, J. F.;Gusain, A.
通讯作者：
Gusain, A.
DOI：
10.1073/pnas.1115484108
发表时间：
2011-12-06
影响因子：
11.1
作者：
Barcelo-Coblijn, Gwendolyn;Laura Martin, Maria;Escriba, Pablo V.
通讯作者：
Escriba, Pablo V.
影响因子：
4.8
作者：
Luberto, C;Hannun, YA
通讯作者：
Hannun, YA
影响因子：
3.6
作者：
Day, Travis W.;Wu, Ching-Huang;Safa, Ahmad R.
通讯作者：
Safa, Ahmad R.
影响因子：
3.3
作者：
BLASI, E;BARLUZZI, R;BISTONI, F
通讯作者：
BISTONI, F