Gómez del Pulgar Teresa, Velasco Guillermo, Sánchez Cristina, Haro Amador, Guzmán Manuel
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain.
Biochem J. 2002 Apr 1;363(Pt 1):183-8. doi: 10.1042/0264-6021:3630183.
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 de 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.
Δ⁹-四氢大麻酚（THC）及其他大麻素已被证明可通过神经酰胺生成诱导胶质瘤细胞凋亡。在本研究中，我们使用C6胶质瘤细胞的两个亚克隆研究了负责这种大麻素诱导凋亡的神经酰胺的代谢来源：C6.9，对THC诱导的凋亡敏感；以及C6.4，对THC诱导的凋亡具有抗性。从头合成神经酰胺的药理学抑制，而非中性和酸性鞘磷脂酶的抑制，可预防C6.9细胞中THC诱导的凋亡。催化从头合成神经酰胺限速步骤的丝氨酸棕榈酰转移酶（SPT）的活性在C6.9细胞中被THC显著增强，但在C6.4细胞中未增强。然而，SPT mRNA和蛋白水平未见明显变化。SPT活性的变化与神经酰胺水平的变化平行。从头合成神经酰胺的药理学抑制也可预防大麻素触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了大麻素诱导的胶质瘤细胞凋亡。
