Src-mediated aryl hydrocarbon and epidermal growth factor receptor cross talk stimulates colon cancer cell proliferation.
Src-mediated aryl hydrocarbon and epidermal growth factor receptor cross talk stimulates colon cancer cell proliferation.
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DOI：
10.1152/ajpgi.00427.2011
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发表时间：
2012-05
期刊：
影响因子：
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通讯作者：
G. Xie;Zhongsheng Peng;J. Raufman
中科院分区：
文献类型：
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作者：
G. Xie;Zhongsheng Peng;J. Raufman
芳香烃受体(AhR)介导环境污染物的多种毒性效应。AHR还与多种生长因子驱动的信号通路相互作用。在检测生长因子对人结肠癌细胞增殖的影响的过程中，我们发现AhR和表皮生长因子受体(EGFR)之间存在串扰。在目前的工作中，我们探索了这种相互作用的潜在信号转导机制和功能后果。以人结肠癌细胞株H508和SNU-C4为研究对象，研究了包括2，3，7，8-四氯二苯并-对二恶英(TCDD)在内的AhR配体对细胞增殖和EGFR、ERK1/2和Src激酶活性的影响。在结肠癌细胞中，与TCDD孵育5天，细胞增殖增加两倍，呈剂量依赖关系，1 NM可检测到，30 NM TCDD最大。TCDD诱导EGFR(Tyr845)和ERK1/2的磷酸化呈剂量和时间依赖性，在加入30 nM TCDD后5~10min达到最大磷酸化。AhR小干扰RNA、AhR特异性抑制剂CH223191、Src激酶抑制剂PP2、基质金属蛋白酶7中和抗体、肝素结合EGF样生长因子和EGFR、EGFR抑制剂(AG1478和PD168393)以及MEK1抑制剂PD98059均可阻断TCDD诱导的ERK1/2磷酸化和细胞增殖。免疫共沉淀实验表明AhR与Src形成蛋白质复合体，通过磷酸化Src(Tyr416)和去磷酸化Src(Tyr527)来调节Src的活性。这些数据支持了新的观察结果，即在人类结肠癌细胞中，Src介导的芳烃和EGFR之间的串扰导致ERK1/2激活，从而刺激细胞增殖。
The aryl hydrocarbon receptor (AhR) mediates many toxic effects of environmental pollutants. AhR also interacts with multiple growth factor-driven signaling pathways. In the course of examining effects of growth factors on proliferation of human colon cancer cells, we identified cross talk between AhR and the epidermal growth factor receptor (EGFR). In the present work, we explored underlying signal transduction mechanisms and functional consequences of this interaction. With the use of two human colon cancer cell lines, H508 and SNU-C4, we examined the effects of AhR ligands including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on cell proliferation and activation of EGFR, ERK1/2, and Src kinases. In colon cancer cells, 5-day incubation with TCDD stimulated a twofold dose-dependent increase in cell proliferation that was detectable with 1 nM and maximal with 30 nM TCDD. TCDD induced dose- and time-dependent phosphorylation of EGFR (Tyr845) and ERK1/2; maximal phosphorylation was observed 5 to 10 min after addition of 30 nM TCDD. Both TCDD-induced ERK1/2 phosphorylation and cell proliferation were abolished by AhR small interfering RNA, AhR-specific inhibitor CH223191, Src kinase inhibitor PP2, neutralizing antibodies against matrix metalloproteinase 7, heparin-binding-EGF-like growth factor and EGFR, EGFR inhibitors (AG1478 and PD168393), and MEK1 inhibitor PD98059. Coimmunoprecipitation experiments revealed that AhR forms a protein complex with Src and regulates Src activity by phosphorylating Src (Tyr416) and dephosphorylating Src (Tyr527). These data support novel observations that, in human colon cancer cells, Src-mediated cross talk between aryl hydrocarbon and EGFR results in ERK1/2 activation, thereby stimulating cell proliferation.