De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis
De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis
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DOI：
10.1042/0264-6021:3630183
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发表时间：
2002-04-01
影响因子：
4.1
通讯作者：
Guzmán, M
中科院分区：
文献类型：
--
作者：
del Pulgar, TG;Velasco, G;Guzmán, M
Delta(9)-四氢大麻酚 (THC) 和其他大麻素已被证明可通过神经酰胺的生成诱导神经胶质瘤细胞凋亡。在本研究中，我们通过使用 C6 神经胶质瘤细胞的两个亚克隆来研究负责这种大麻素诱导的细胞凋亡的神经酰胺的代谢起源：C6.9，对 THC 诱导的细胞凋亡敏感；C6.9，它对 THC 诱导的细胞凋亡敏感；和 C6.4，它能抵抗 THC 诱导的细胞凋亡。对神经酰胺从头合成的药理抑制，但对中性和酸性鞘磷脂酶的抑制，可以阻止 THC 诱导的 C6.9 细胞凋亡。 THC 在 C6.9 细胞中显着增强了丝氨酸棕榈酰转移酶 (SPT) 的活性，该酶催化神经酰胺从头合成的限速步骤，但在 C6.4 细胞中则不然。然而，SPT mRNA 和蛋白质水平没有明显的重大变化。 SPT 活性的变化与神经酰胺水平的变化平行，神经酰胺从头合成的药理抑制也阻止了大麻素引发的细胞外信号调节激酶的刺激和蛋白激酶 B 的抑制。这些发现表明，从头合成的神经酰胺参与大麻素诱导的神经胶质瘤细胞凋亡。
Delta(9)-Tetrahydrocannabinol (THC) and other cannabinoids have been shown to induce apoptosis of glioma cells via ceramide generation. In the present study, we investigated the metabolic origin of the ceramide responsible for this cannabinoid-induced apoptosis by using two subclones of C6 glioma cells: C6.9, which is sensitive to THC-induced apoptosis; and C6.4, which is resistant to THC-induced apoptosis. Pharmacological inhibition of ceramide synthesis de novo, but not of neutral and acid sphingomyelinases, prevented THC-induced apoptosis in C6.9 cells. The activity of serine palmitoyltransferase (SPT), which catalyses the rate-limiting step of ceramide synthesis tie novo, was remarkably enhanced by THC in C6.9 cells, but not in C6.4 cells. However, no major changes in SPT mRNA and protein levels were evident. Changes in SPT activity paralleled changes in ceramide levels, Pharmacological inhibition of ceramide synthesis de novo also prevented the stimulation of extracellular-signal-regulated kinase and the inhibition of protein kinase B triggered by cannabinoids. These findings show that de novo-synthesized ceramide is involved in cannabinoid-induced apoptosis of glioma cells.