Epidermal growth factor receptor inhibitors enhance susceptibility to Fas-mediated apoptosis in oral squamous cell carcinoma cells
Epidermal growth factor receptor inhibitors enhance susceptibility to Fas-mediated apoptosis in oral squamous cell carcinoma cells
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DOI：
10.1016/j.oraloncology.2007.04.006
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发表时间：
2008-04-01
期刊：
影响因子：
4.8
通讯作者：
Nagumo, Masao
中科院分区：
文献类型：
--
作者：
Iwase, Masayasu;Takaoka, Sayaka;Nagumo, Masao
表皮生长因子受体（EGFR）信号传导的分子抑制是一种有前途的癌症治疗策略。我们研究了EGFR信号的抑制是否会影响口腔鳞状细胞癌（OSCC）细胞对Fas介导的凋亡的易感性。用抗EGFR单克隆抗体C225和EGFR酪氨酸激酶抑制剂AG 1478治疗OSCC细胞，分别靶向EGFR的细胞外和细胞内结构域，抑制EGFR及其下游效应分子Akt的磷酸化，并增强Fas介导的凋亡诱导。在用EGFR抑制剂处理的OSCC细胞中，Fas介导的凋亡伴随着caspase-8激活，但不伴随Bid裂解。Caspase-3和Caspase-8抑制剂降低EGFR抑制剂对Fas介导的OSCC细胞凋亡的影响，但Caspase-9抑制剂没有。这些结果表明EGFR抑制剂在OSCC细胞中的促凋亡活性依赖于caspase级联反应的外源性途径。虽然EGFR抑制剂不影响Fas，Fas相关的死亡结构域蛋白，或在OSCC细胞中的半胱氨酸天冬氨酸蛋白酶-8的表达，抑制下调细胞FLICE抑制蛋白（c-FLIP）。此外，在HSC-2细胞中用小干扰RNA敲低c-FLIP强烈增强Fas介导的凋亡。这些结果表明，EGFR信号通路可能，部分，通过c-FLIP表达调控Fas介导的凋亡在口腔鳞癌细胞。(C)2007爱思唯尔有限公司保留所有权利。
Molecular inhibition of epidermal growth factor receptor (EGFR) signaling is a promising cancer treatment strategy. We examined whether inhibition of EGFR signaling would affect the susceptibility of oral squamous cell carcinoma (OSCC) cells to Fas-mediated apoptosis. Treatment of OSCC cells with an anti-EGFR monoclonal antibody, C225, and an EGFR tyrosine kinase inhibitor, AG1478, which target the extracellular and intracellular domains of the receptor, respectively, inhibited phosphorylation of EGFR and its downstream effector molecule Akt and amplified the induction of Fas-mediated apoptosis. In OSCC cells treated with EGFR inhibitors, Fas-mediated apoptosis was accompanied by caspase-8 activation but not Bid cleavage. Caspase-3 and -8 inhibitors reduced the effect of EGFR inhibitors on Fas-mediated apoptosis in OSCC cells, but a caspase-9 inhibitor did not. These results indicate that the pro-apoptotic activity of EGFR inhibitors in OSCC cells depends on the extrinsic pathway of the caspase cascade. Although EGFR inhibitors did not affect the expression of Fas, the Fas-associated death domain protein, or procaspase-8 in OSCC cells, the inhibition downregulated cellular FLICE-inhibitory protein (c-FLIP). Moreover, knockdown of c-FLIP in HSC-2 cells with a small interfering RNA strongly enhanced Fas-mediated apoptosis. These results suggest that the EGFR signaling pathway may, in part, regulate Fas-mediated apoptosis in OSCC cells through c-FLIP expression. (C) 2007 Elsevier Ltd. All rights reserved.