TRAIL-activated EGFR by Cbl-b-regulated EGFR redistribution in lipid rafts antagonises TRAIL-induced apoptosis in gastric cancer cells
TRAIL-activated EGFR by Cbl-b-regulated EGFR redistribution in lipid rafts antagonises TRAIL-induced apoptosis in gastric cancer cells
复制标题
Cbl-b 调节脂筏中 EGFR 重新分布，TRAIL 激活 EGFR 拮抗 TRAIL 诱导的胃癌细胞凋亡
DOI：
10.1016/j.ejca.2012.03.005
复制
发表时间：
2012-11-01
影响因子：
8.4
通讯作者：
Liu, Yunpeng
中科院分区：
文献类型：
--
作者：
Xu, Ling;Zhang, Ye;Liu, Yunpeng
大多数胃癌细胞对肿瘤坏死因子相关凋亡诱导配体（TRAIL）具有耐药性。由于TRAIL耐药与脂筏相关，其中死亡受体和表皮生长因子受体（EGFR）都富集，我们的目的是确定脂筏调节的受体再分布如何影响胃癌细胞中TRAIL的敏感性。在TRAIL耐药的胃癌细胞中，TRAIL不能诱导脂筏中有效的死亡诱导信号复合物（DISC）的形成，并伴随EGFR易位到脂筏中，以及EGFR通路的激活。casitas B-谱系淋巴瘤-b（Cbl-b）的敲除通过促进脂筏中DISC的形成来增强TRAIL诱导的细胞凋亡。然而，Cbl-b的敲低也增强了EGFR向脂筏的移位和由TRAIL诱导的EGFR途径激活。使用EGFR抑制剂或用小干扰RNA（siRNA）耗尽EGFR阻止EGFR通路活化，从而增加TRAIL诱导的细胞凋亡，特别是在Cbl-b敲低克隆中。总之，通过Cbl-b调节EGFR在脂筏中的再分布，TRAIL诱导的EGFR活化拮抗了TRAIL诱导的细胞凋亡。DISC的形成和脂筏中EGFR信号的抑制是增加胃癌细胞对TRAIL敏感性的关键。(C)2012爱思唯尔有限公司保留所有权利。
Most gastric cancer cells are resistant to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Since TRAIL resistance is associated with lipid rafts, in which both death receptors and epidermal growth factor receptors (EGFR) are enriched, our aim is to identify how lipid raft-regulated receptor redistribution influences the sensitivity of TRAIL in gastric cancer cells. In TRAIL-resistant gastric cancer cells, TRAIL did not induce effective death-inducing signalling complex (DISC) formation in lipid rafts, accompanied with EGFR translocation into lipid rafts, and activation of EGFR pathway. Knockdown of casitas B-lineage lymphoma-b (Cbl-b) enhanced TRAIL-induced apoptosis by promoting DISC formation in lipid rafts. However, knockdown of Cbl-b also enhanced EGFR translocation into lipid rafts and EGFR pathway activation induced by TRAIL. Either using inhibitors of EGFR or depletion of EGFR with small interfering RNA (siRNA) prevented EGFR pathway activation, and thus increased TRAIL-induced apoptosis, especially in Cbl-b knockdown clones. Taken together, TRAIL-induced EGFR activation through Cbl-b-regulated EGFR redistribution in lipid rafts antagonised TRAIL-induced apoptosis. The contribution of DISC formation and the inhibition of EGFR signal triggered in lipid rafts are both essential for increasing the sensitivity of gastric cancer cells to TRAIL. (C) 2012 Elsevier Ltd. All rights reserved.