Proapoptotic BH3-only BCL-2 family protein BIM connects death signaling from epidermal growth factor receptor inhibition to the mitochondrion
Proapoptotic BH3-only BCL-2 family protein BIM connects death signaling from epidermal growth factor receptor inhibition to the mitochondrion
复制标题
DOI：
10.1158/0008-5472.can-07-1961
复制
发表时间：
2007-12-15
期刊：
影响因子：
11.2
通讯作者：
Letai, Anthony
中科院分区：
文献类型：
--
作者：
Deng, Jing;Shimamura, Takeshi;Letai, Anthony
肺癌的一个子集表达组成性激活的表皮生长因子受体（EGFR）的突变形式。携带活化EGFR的癌症可以用EGFR抑制剂如厄洛替尼有效靶向。然而，EGFR抑制后参与的死亡信号通路知之甚少。在这里，我们表明，EGFR抑制后的死亡使用由BCL-2蛋白家族控制的线粒体或内在细胞死亡途径。BCL-2抑制厄洛替尼诱导的细胞死亡，但BCL-2保护的细胞因此呈现BCL-2依赖性并对BCL-2拮抗剂ABT-737敏感。BH 3分析表明，在这些细胞中EGFR抑制后，线粒体BCL-2被死亡信号引发。这一结果表明，BCL-2家族的关键死亡信号蛋白，包括RIM，在厄洛替尼治疗后被上调，并被过表达的BCL-2拦截。BIM由对厄洛替尼敏感的肺癌细胞系诱导，而不是由耐药的肺癌细胞系诱导。通过siRNA减少BIM诱导对厄洛替尼的抗性。我们发现，EGFR活性抑制厄洛替尼在H1650，一个肺癌细胞系，具有致敏EGFR突变，但141650没有被杀死。我们确定了该细胞系中细胞凋亡的阻断，并表明存在一种新形式的厄洛替尼抗性，即EGFR抑制下游BIM上调的阻断。这一发现对克服厄洛替尼耐药性具有明确的意义。对EGFR抑制的抗性可以通过由BCL-2蛋白家族控制的内在凋亡途径的改变来调节。
A subset of lung cancers expresses mutant forms of epidermal growth factor receptor (EGFR) that are constitutively activated. Cancers bearing activated EGFR can be effectively targeted with EGFR inhibitors such as erlotinib. However, the death-signaling pathways engaged after EGFR inhibition are poorly understood. Here, we show that death after inhibition of EGFR uses the mitochondrial, or intrinsic, pathway of cell death controlled by the BCL-2 family of proteins. BCL-2 inhibits cell death induced by erlotinib, but BCL-2-protected cells are thus rendered BCL-2-dependent and sensitive to the BCL-2 antagonist ABT-737. BH3 profiling reveals that mitochondrial BCL-2 is primed by death signals after EGFR inhibition in these cells. As this result implies, key death-signaling proteins of the BCL-2 family, including RIM, were found to be up-regulated after erlotinib treatment and intercepted by over-expressed BCL-2. BIM is induced by lung cancer cell lines that are sensitive to erlotinib but not by those resistant. Reduction of BIM by siRNA induces resistance to erlotinib. We show that EGFR activity is inhibited by erlotinib in H1650, a lung cancer cell line that bears a sensitizing EGFR mutation, but that 141650 is not killed. We identify the block in apoptosis in this cell line, and show that a novel form of erlotinib resistance is present, a block in BIM up-regulation downstream of EGFR inhibition. This finding has clear implications for overcoming resistance to erlotinib. Resistance to EGFR inhibition can be modulated by alterations in the intrinsic apoptotic pathway controlled by the BCL-2 family of proteins.