ABINs inhibit EGF receptor-mediated NF-κB activation and growth of EGF receptor-overexpressing tumour cells
ABINs inhibit EGF receptor-mediated NF-κB activation and growth of EGF receptor-overexpressing tumour cells
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DOI：
10.1038/onc.2008.208
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发表时间：
2008-10-01
期刊：
影响因子：
8
通讯作者：
Beyaert, R.
中科院分区：
文献类型：
--
作者：
Huang, L.;Verstrepen, L.;Beyaert, R.
表皮生长因子受体（EGFR）在各种起源于表皮的肿瘤中经常过表达，并被认为是致瘤性和肿瘤持久性的原因。核因子(NF)- κ B活性的增加被认为与egfr过表达细胞的恶性行为有关。然而，调控egf诱导的NF-kappa B活化的机制在很大程度上仍然未知。本研究表明，在egfr过表达的HEK293T细胞中，EGF可以诱导nf - κ B依赖性基因表达，而不依赖于I κ B α降解或p100加工。此外，egf诱导的NF-kappa B激活可以被ABINs的过表达抑制，ABINs先前被鉴定为肿瘤坏死因子、白细胞介素-1和脂多糖诱导的NF-kappa B激活的细胞内抑制剂。通过RNA干扰敲低ABIN-1可增强NF-kappa B对EGF刺激的反应。ABINs的c端泛素结合域是抑制NF-kappa B的关键和充分区域。ABINs的腺病毒基因转移降低了组成NF-kappa B活性以及过表达egfr的A431和DU145人癌细胞的增殖。总之，这些结果证明了ABIN敏感的非经典NF-kappa B信号通路在egfr过表达肿瘤细胞增殖中的重要作用，并表明了ABIN基因治疗在癌症治疗中的潜在用途。
The epidermal growth factor receptor (EGFR) is frequently overexpressed in various tumours of epidermal origin and is held responsible for tumourigenicity and tumour persistence. Increased nuclear factor (NF)-kappa B activity has been suggested to be involved in the malignant behaviour of EGFR-overexpressing cells. However, the mechanisms that regulate EGF-induced NF-kappa B activation are still largely unknown. Here we show that EGF can induce NF-kappa B-dependent gene expression independently from I kappa B alpha degradation or p100 processing in EGFR-overexpressing HEK293T cells. Moreover, EGF-induced NF-kappa B activation could be inhibited by overexpression of ABINs, which were previously identified as intracellular inhibitors of tumour necrosis factor, interleukin-1 and lipopolysaccharide-induced NF-kappa B activation. Knockdown of ABIN-1 by RNA interference boosted the NF-kappa B response upon EGF stimulation. The C-terminal ubiquitin-binding domain containing region of ABINs was crucial and sufficient for NF-kappa B inhibition. Adenoviral gene transfer of ABINs reduced constitutive NF-kappa B activity as well as the proliferation of EGFR-overexpressing A431 and DU145 human carcinoma cells. Altogether, these results demonstrate an important role for an ABIN-sensitive non-classical NF-kappa B signalling pathway in the proliferation of EGFR-overexpressing tumour cells, and indicate a potential use for ABIN gene therapy in the treatment of cancer.