Notch3 cooperates with the EGFR pathway to modulate apoptosis through the induction of bim.
Notch3 cooperates with the EGFR pathway to modulate apoptosis through the induction of bim.
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DOI：
10.1038/onc.2009.366
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发表时间：
2010-01-28
期刊：
影响因子：
8
通讯作者：
Dang, T. P.
中科院分区：
文献类型：
--
作者：
Konishi, J.;Yi, F.;Chen, X.;Vo, H.;Carbone, D. P.;Dang, T. P.
Notch信号传导是一种高度保守的途径，对正常胚胎发育和癌症都很重要。我们先前证明了Notch 3在肺癌发病机制中的作用。Notch 3抑制导致肿瘤细胞凋亡和生长抑制。在体外，当EGFR途径也被抑制时，这些作用增强，表明这两种途径之间存在显著的串扰。Notch 3和EGFR/MAPK通路如何协同调节细胞凋亡尚不清楚。在这项研究中，我们提供的证据表明，Notch 3调节Bim，BH-3唯一的蛋白通过MAPK信号。此外，Bim表达的丧失阻止了Notch 3抑制诱导的肿瘤细胞凋亡。在异种移植模型中使用γ-分泌酶抑制剂和厄洛替尼，与单独使用任一种药物相比，Bim诱导和肿瘤抑制增强，这与我们先前观察到的Notch和EGFR/ras/MAPK信号传导之间的显著协同作用一致。因此，我们的数据支持Notch 3不仅通过调节细胞凋亡在肺癌中起关键作用，而且还与EGFR/MAPK通路合作调节Bim的假设。
Notch signaling is a highly conserved pathway important for normal embryonic development and as well as cancer. We previously demonstrated a role for Notch3 in lung cancer pathogenesis. Notch3 inhibition resulted in tumor apoptosis and growth suppression. In vitro, these effects were enhanced when the EGFR pathway was also inhibited, suggesting significant crosstalk between these two pathways. How Notch3 and EGFR/MAPK pathways cooperate in modulating apoptosis is not yet known. In this study, we provide evidence that Notch3 regulates Bim, a BH-3-only protein via MAPK signaling. Furthermore, loss of Bim expression prevents tumor apoptosis induced by Notch3 inhibition. Using γ-secretase inhibitor and erlotinib in a xenograft model, Bim induction and tumor inhibition were enhanced compared to either agent alone, consistent with our previous observation of significant synergism between Notch and EGFR/ras/MAPK signaling. Thus, our data support the hypothesis that Notch3 not only plays a crucial role in lung cancer through regulating apoptosis but also cooperates with the EGFR/MAPK pathway in modulating Bim.
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BIM的诱导对于突变体EGFR依赖性肺腺癌中EGFR激酶抑制剂触发的凋亡至关重要。
影响因子：
15.8
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