文章：

脂质筏介导的Akt信号作为套细胞淋巴瘤的治疗靶点

Lipid raft-mediated Akt signaling as a therapeutic target in mantle cell lymphoma

原文发布日期：2013-05-31

DOI: 10.1038/bcj.2013.15

类型: Original Article

开放获取: 是

英文摘要：

Recent evidence shows that lipid raft membrane domains modulate both cell survival and death. Here, we have found that the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is present in the lipid rafts of mantle cell lymphoma (MCL) cells, and this location seems to be critical for full activation and MCL cell survival. The antitumor lipids (ATLs) edelfosine and perifosine target rafts, and we found that ATLs exerted in vitro and in vivo antitumor activity against MCL cells by displacing Akt as well as key regulatory kinases p-PDK1 (phosphatidylinositol-dependent protein kinase 1), PI3K and mTOR (mammalian TOR) from lipid rafts. This raft reorganization led to Akt dephosphorylation, while proapoptotic Fas/CD95 death receptor was recruited into rafts. Raft integrity was critical for Ser473 Akt phosphorylation. ATL-induced apoptosis appeared to correlate with the basal Akt phosphorylation status in MCL cell lines and primary cultures, and could be potentiated by the PI3K inhibitor wortmannin, or inhibited by the Akt activator pervanadate. Classical Akt inhibitors induced apoptosis in MCL cells. Microenvironmental stimuli, such as CD40 ligation or stromal cell contact, did not prevent ATL-induced apoptosis in MCL cell lines and patient-derived cells. These results highlight the role of raft-mediated PI3K/Akt signaling in MCL cell survival and chemotherapy, thus becoming a new target for MCL treatment.

摘要翻译： 

近期证据表明，脂质筏膜域同时调节细胞存活与死亡。本研究发现，磷脂酰肌醇-3-激酶（PI3K）/Akt信号通路存在于套细胞淋巴瘤（MCL）细胞的脂质筏中，且该定位对信号通路的完全激活及MCL细胞存活至关重要。抗肿瘤脂质类药物艾德福新和佩里福辛以脂质筏为靶点，我们发现这类药物通过将Akt及其关键调节激酶p-PDK1（磷脂酰肌醇依赖性蛋白激酶1）、PI3K和mTOR（哺乳动物雷帕霉素靶蛋白）从脂质筏中置换出来，从而在体外和体内对MCL细胞发挥抗肿瘤活性。这种脂质筏重组导致Akt去磷酸化，同时促凋亡Fas/CD95死亡受体被募集至脂质筏。脂质筏完整性对Akt Ser473位点磷酸化至关重要。抗肿瘤脂质诱导的细胞凋亡与MCL细胞系及原代培养物中Akt的基础磷酸化水平相关，并可被PI3K抑制剂渥曼青霉素增强，或被Akt激活剂过钒酸盐抑制。经典Akt抑制剂可诱导MCL细胞凋亡。微环境刺激（如CD40交联或基质细胞接触）不能阻止抗肿瘤脂质在MCL细胞系及患者来源细胞中诱导的凋亡。这些研究结果凸显了脂质筏介导的PI3K/Akt信号通路在MCL细胞存活及化疗应答中的重要作用，使其成为MCL治疗的新靶点。

原文链接：

Lipid raft-mediated Akt signaling as a therapeutic target in mantle cell lymphoma