Abstract
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)-κB activity has been suggested to be involved in the malignant behaviour of EGFR-overexpressing cells. However, the mechanisms that regulate EGF-induced NF-κB activation are still largely unknown. Here we show that EGF can induce NF-κB-dependent gene expression independently from IκBα degradation or p100 processing in EGFR-overexpressing HEK293T cells. Moreover, EGF-induced NF-κB 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-κB activation. Knockdown of ABIN-1 by RNA interference boosted the NF-κB response upon EGF stimulation. The C-terminal ubiquitin-binding domain containing region of ABINs was crucial and sufficient for NF-κB inhibition. Adenoviral gene transfer of ABINs reduced constitutive NF-κB 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-κB signalling pathway in the proliferation of EGFR-overexpressing tumour cells, and indicate a potential use for ABIN gene therapy in the treatment of cancer.
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Acknowledgements
This work was supported in part by grants from the ‘Interuniversitaire Attractiepolen’ (IAP6/18), the ‘Fonds voor Wetenschappelijk Onderzoek-Vlaanderen’ (FWO-Vlaanderen), the GOA of the University of Gent. LH is a predoctoral research fellow supported by the IWT-Vlaanderen and the Emmanuel Vanderschueren Stichting.
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Huang, L., Verstrepen, L., Heyninck, K. et al. ABINs inhibit EGF receptor-mediated NF-κB activation and growth of EGF receptor-overexpressing tumour cells. Oncogene 27, 6131–6140 (2008). https://doi.org/10.1038/onc.2008.208
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DOI: https://doi.org/10.1038/onc.2008.208
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