The two first authors contributed equally to this work.
The metalloproteinase ADAM-12 regulates bronchial epithelial cell proliferation and apoptosis
Article first published online: 6 OCT 2008
© 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd
Volume 41, Issue 6, pages 988–1001, December 2008
How to Cite
Rocks, N., Estrella, C., Paulissen, G., Quesada-Calvo, F., Gilles, C., Guéders, M. M., Crahay, C., Foidart, J.-M., Gosset, P., Noel, A. and Cataldo, D. D. (2008), The metalloproteinase ADAM-12 regulates bronchial epithelial cell proliferation and apoptosis. Cell Proliferation, 41: 988–1001. doi: 10.1111/j.1365-2184.2008.00557.x
- Issue published online: 18 NOV 2008
- Article first published online: 6 OCT 2008
- Received 29 October 2007; revision accepted 17 March 2008
Abstract. Objectives: The ADAMs (a disintegrin and metalloproteinase) enzymes compose a family of membrane-bound proteins characterized by their multi-domain structure and ADAM-12 expression is elevated in human non-small cell lung cancers. The aim of this study was to investigate the roles played by ADAM-12 in critical steps of bronchial cell transformation during carcinogenesis. Materials and methods: To assess the role of ADAM-12 in tumorigenicity, BEAS-2B cells were transfected with a plasmid encoding human full-length ADAM-12 cDNA, and then the effects of ADAM-12 overexpression on cell behaviour were explored. Treatment of clones with heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) neutralizing antibodies as well as an EGFR inhibitor allowed the dissection of mechanisms regulating cell proliferation and apoptosis. Results: Overexpression of ADAM-12 in BEAS-2B cells promoted cell proliferation. ADAM-12 overexpressing clones produced higher quantities of HB-EGF in their culture medium which may rely on membrane-bound HB-EGF shedding by ADAM-12. Targeting HB-EGF activity with a neutralizing antibody abrogated enhanced cell proliferation in the ADAM-12 overexpressing clones. In sharp contrast, targeting of amphiregulin, EGF or transforming growth factor-α failed to influence cell proliferation; moreover, ADAM-12 transfectants were resistant to etoposide-induced apoptosis and the use of a neutralizing antibody against HB-EGF activity restored rates of apoptosis to be similar to controls.Conclusions: ADAM-12 contributes to enhancing HB-EGF shedding from plasma membranes leading to increased cell proliferation and reduced apoptosis in this bronchial epithelial cell line.