文章：

大麻素通过诱导神经酰胺从头合成介导结直肠癌细胞免疫原性死亡，部分经由CB2受体通路实现

Cannabinoid-Induced Immunogenic Cell Death of Colorectal Cancer Cells Through De Novo Synthesis of Ceramide Is Partially Mediated by CB2 Receptor

原文发布日期：27 November 2024

DOI: 10.3390/cancers16233973

类型: Article

开放获取: 是

英文摘要：

Background:Our recent studies have identified a link between sphingolipid metabolites and the induction of a specialized form of regulated cell death termed immunogenic cell death (ICD). We have recently demonstrated that the synthetic cannabinoid (±) 5-epi CP 55,940 (5-epi) stimulates the accumulation of ceramide (Cer), and that inhibition of sphingosine kinase 1 (SphK1) enhances Cer accumulation and ICD-induction in human colorectal cancer (CRC) cell lines.Methods:We employed flow-cytometric, western blot analyses, pharmacological inhibitors of the sphingolipid metabolic pathway and small molecule agonists and antagonists of the CB receptors to further analyze the mechanism by which 5-epi induces Cer accumulation.Results:Herein, and report that 5-epi induces de novo synthesis of Cer primarily through engagement of the cannabinoid receptor 2 (CB2) and depletion of intracellular calcium levels. Moreover, we report that 5-epi stimulates Cer synthesis through dysregulation of the endogenous inhibitor of the de novo Cer pathway, ORMDL3. We also observed a remarkable and specific accumulation of one Cer species, C20:4 Cer, generated predominantly by ceramide synthase 4, as a key factor required for 5-epi-induced ICD.Conclusions:Together, these data indicate that engagement of CB2, by 5-epi, alters regulation of the de novo ceramide synthesis pathway to generate Cer species that mediate ICD.

摘要翻译： 

背景：我们近期研究发现，鞘脂代谢物与一种特殊形式的调节性细胞死亡——免疫原性细胞死亡（ICD）之间存在关联。最新实验表明，合成大麻素(±)5-epi CP 55,940（5-epi）能刺激神经酰胺（Cer）的积累，而抑制鞘氨醇激酶1（SphK1）可增强人结直肠癌（CRC）细胞系中Cer的积累及ICD诱导。 方法：通过流式细胞术、蛋白质印迹分析、鞘脂代谢通路药理抑制剂以及大麻素受体小分子激动剂与拮抗剂，系统解析5-epi诱导Cer积累的作用机制。 结果：本研究发现5-epi主要通过激活大麻素受体2（CB2）及耗竭细胞内钙离子水平，从而诱导Cer的从头合成。同时证实5-epi通过干扰内源性Cer从头合成通路抑制剂ORMDL3的调控功能来促进Cer合成。实验还观察到由神经酰胺合酶4主导生成的特异性Cer亚型C20:4 Cer的显著积累，这是5-epi诱导ICD所需的关键因子。 结论：综合结果表明，5-epi通过激活CB2受体改变神经酰胺从头合成通路的调控机制，进而产生介导ICD的特异性Cer亚型。

原文链接：

Cannabinoid-Induced Immunogenic Cell Death of Colorectal Cancer Cells Through De Novo Synthesis of Ceramide Is Partially Mediated by CB2 Receptor