Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells
Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells
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DOI：
10.1172/jci37948
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发表时间：
2009-05-01
影响因子：
15.9
通讯作者：
Velasco, Guillermo
中科院分区：
文献类型：
--
作者：
Salazar, Maria;Carracedo, Arkaitz;Velasco, Guillermo
自噬可以促进细胞存活或细胞死亡，但其在癌症中双重作用的分子基础仍然不清楚。在这里，我们证明了δ（9）-四氢大麻酚（THC），大麻的主要活性成分，通过刺激自噬诱导人脑胶质瘤细胞死亡。我们的数据表明，THC诱导神经酰胺积累和真核生物翻译起始因子2 α（eIF 2 α）磷酸化，从而激活ER应激反应，通过tribbles同源物3依赖性（TRB 3依赖性）抑制Akt/哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）轴促进自噬。我们还表明，自噬是大麻素诱导的人类和小鼠癌细胞死亡中细胞凋亡的上游，并且该途径的激活是大麻素体内抗肿瘤作用所必需的。这些发现描述了THC可以促进人类和小鼠癌细胞自噬死亡的机制，并提供了大麻素给药可能是靶向人类癌症的有效治疗策略的证据。
Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure. Here we demonstrate that Delta(9)-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy. Our data indicate that THC induced ceramide accumulation and eukaryotic translation initiation factor 2 alpha (eIF2 alpha) phosphorylation and thereby activated an ER stress response that promoted autophagy via tribbles homolog 3-dependent (TRB3-dependent) inhibition of the Akt/mammalian target of rapamycin complex 1 (mTORC1) axis. We also showed that autophagy is upstream of apoptosis in cannabinoid-induced human and mouse cancer cell death and that activation of this pathway was necessary for the antitumor action of cannabinoids in vivo. These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers.