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ABINs inhibit EGF receptor-mediated NF-κB activation and growth of EGF receptor-overexpressing tumour cells

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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