Differential regulation of cell death in head and neck cell carcinoma through alteration of cholesterol levels in lipid rafts microdomains
Differential regulation of cell death in head and neck cell carcinoma through alteration of cholesterol levels in lipid rafts microdomains
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DOI：
10.1016/j.bcp.2007.10.004
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发表时间：
2008-02-01
影响因子：
5.8
通讯作者：
Ardail, Dominique
中科院分区：
文献类型：
--
作者：
Bionda, Clara;Athias, Anne;Ardail, Dominique
脂筏是细胞膜上富含胆固醇的微区。它们作为分子平台，在空间上组织膜受体分子，并参与各种信号转导途径。我们最近报道，在放射敏感的鳞状细胞癌SCC 61线，γ-照射的结果在质膜筏和信号平台的重排，导致辐射诱导的神经酰胺依赖性途径的细胞凋亡。相比之下，发现这种重组在抗辐射对应细胞系SQ 20 B中是有缺陷的。由于SQ 20 B中脂筏的胆固醇含量是SCC 61细胞的两倍，因此我们研究了使用甲基-β-环糊精（M β CDX）（一种广泛使用的胆固醇消耗剂）对这些微结构域的调节，以破坏两种细胞中的筏组织。在这里，我们报告说，M β CDX治疗导致在SCC 61细胞中涉及线粒体事件的细胞凋亡的触发，并与Fas的聚集，形成Fas-FADD复合物和蛋白酶原8的裂解。这种死亡受体的配体非依赖性激活在SQ 20 B细胞中完全不存在，SQ 20 B细胞仍然对M β CDX触发的凋亡具有抗性。然而，用M β CDX处理SQ 20 B导致表皮生长因子受体（EGFR）存活途径的配体非依赖性激活，如EGFR酪氨酸磷酸化增加所证明的。总之，我们的研究结果表明，脂质筏的完整性密切参与触发头颈部癌细胞的凋亡细胞死亡和/或生存途径。(c)2007年爱思唯尔公司All rights reserved.
Lipid rafts are cholesterol-enriched microdomains in the plasma membrane. They act as molecular platforms that spatially organize membrane receptor molecules and are involved in the transduction of various signaling pathways. We recently reported that in the radiosensitive squamous cell carcinoma SCC61 line, gamma-irradiation results in a rearrangement of the plasma membrane rafts and signaling platforms leading to radiation-induced apoptosis in a ceramide-dependent pathway. By contrast, this reorganization was found to be defective in the radioresistant counterpart cell line, SQ20B. As the cholesterol content of lipid rafts is two times higher in SQ20B compared with SCC61 cells, we investigated the modulation of these microdomains using methyl-beta-cyclodextrin (M beta CDX), a widely used cholesterol-depleting agent, in order to disrupt raft organization in both cells. Here, we report that M beta CDX treatment resulted in the triggering of apoptosis in SCC61 cells involving mitochondrial events and associated with the clustering of Fas, the formation of Fas-FADD complexes and the cleavage of procaspase 8. The ligand-independent activation of this death receptor was totally absent in SQ20B cells, which remained resistant to M beta CDX-triggered apoptosis. However, treatment of SQ20B with M beta CDX resulted in a ligand-independent activation of the epidermal growth factor receptor (EGFR) survival pathway, as evidenced by an increased tyrosine phosphorylation of EGFR. Taken altogether, our results indicate that lipid raft integrity is intimately involved in the triggering of apoptotic cell death and/or survival pathways in head and neck carcinoma cells. (c) 2007 Elsevier Inc. All rights reserved.