The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway
The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway
复制标题
DOI：
10.1016/j.yexcr.2006.03.009
复制
发表时间：
2006-07-01
影响因子：
3.7
通讯作者：
Velasco, Guillermo
中科院分区：
文献类型：
--
作者：
Herrera, Blanca;Carracedo, Arkaitz;Velasco, Guillermo
δ(9)-四氢大麻酚和其他大麻素通过CB2大麻素受体在肿瘤细胞中发挥促凋亡作用。然而，涉及到这种效应的分子机制仍然是难以捉摸的。在这里，我们使用表达CB2作为独特的CB受体的人类白血病细胞系jurkat来研究这一机制。我们的研究结果表明，选择性CB2拮抗剂SR144528可以消除Delta(9)-四氢大麻酚的促凋亡作用。大麻素处理导致CB2受体依赖的神经酰胺生物合成刺激，抑制该途径阻止了Delta(9)-四氢大麻酚诱导的线粒体低极化和细胞色素c释放，表明神经酰胺在线粒体前水平起作用。神经酰胺合成的抑制也阻止了caspase的激活和细胞凋亡。Caspase 8激活-一个典型的与外源性凋亡途径相关的事件-在该模型中也很明显。然而，这种蛋白酶的激活是线粒体后的，因为(i)泛caspase抑制剂和选择性caspase 8抑制剂无法阻止Delta(9)-四氢大麻酚诱导的线粒体膜跨膜电位的丧失，（ii）大麻素诱导的caspase 8激活在Bcl-x(L)过表达的细胞中未观察到。综上所述，本研究的结果表明，CB2受体的激活通过对线粒体内在途径的神经酰胺依赖性刺激来信号细胞凋亡。(c) 2006爱思唯尔公司版权所有。
Delta(9)-Tetrahydrocannabinol and other cannabinoids exert pro-apoptotic actions in tumor cells via the CB2 cannabinoid receptor. However, the molecular mechanism involved in this effect has remained elusive. Here we used the human leukemia cell line Jurkat-that expresses CB2 as the unique CB receptor-to investigate this mechanism. Our results show that incubation with the selective CB2 antagonist SR144528 abrogated the pro-apoptotic effect of Delta(9)-tetrahydrocannabinol. Cannabinoid treatment led to a CB2 receptor-dependent stimulation of ceramide biosynthesis and inhibition of this pathway prevented Delta(9)-tetrahydrocannabinol-induced mitochondrial hypopolarization and cytochrome c release, indicating that ceramide acts at a pre-mitochondrial level. inhibition of ceramide synthesis de novo also prevented caspase activation and apoptosis. Caspase 8 activation-an event typically related with the extrinsic apoptotic pathway-was also evident in this model. However, activation of this protease was post-mitochondrial since (i) a pan-caspase inhibitor as well as a selective caspase 8 inhibitor were unable to prevent Delta(9)-tetrahydrocannabinol-induced loss of mitochondrial-membrane transmembrane potential, and (ii) cannabinoid-induced caspase 8 activation was not observed in Bcl-x(L) over-expressing cells. in summary, results presented here show that CB2 receptor activation signals apoptosis via a ceramide-dependent stimulation of the mitochondrial intrinsic pathway. (c) 2006 Elsevier Inc. All rights reserved.