Journal Article

Redox mechanisms switch on hypoxia-dependent epithelial–mesenchymal transition in cancer cells

Stefania Cannito, Erica Novo, Alessandra Compagnone, Lorenzo Valfrè di Bonzo, Chiara Busletta, Elena Zamara, Claudia Paternostro, Davide Povero, Andrea Bandino, Francesca Bozzo, Carlo Cravanzola, Vittoria Bravoco, Sebastiano Colombatto and Maurizio Parola

in Carcinogenesis

Volume 29, issue 12, pages 2267-2278
Published in print December 2008 | ISSN: 0143-3334
Published online September 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn216
Redox mechanisms switch on hypoxia-dependent epithelial–mesenchymal transition in cancer cells

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Epithelial–mesenchymal transition (EMT) and hypoxia are considered as crucial events favouring invasion and metastasis of many cancer cells. In this study, different human neoplastic cell lines of epithelial origin were exposed to hypoxic conditions in order to investigate whether hypoxia per se may trigger EMT programme as well as to mechanistically elucidate signal transduction mechanisms involved. The following human cancer cell lines were used: HepG2 (from human hepatoblastoma), PANC-1 (from pancreatic carcinoma), HT-29 (from colon carcinoma) and MCF-7 (from breast carcinoma). Cancer cells were exposed to carefully controlled hypoxic conditions and investigated for EMT changes and signal transduction by using morphological, cell and molecular biology techniques. All cancer cells responded to hypoxia within 72 h by classic EMT changes (fibroblastoid phenotype, SNAIL and β-catenin nuclear translocation and changes in E-cadherin) and by increased migration and invasiveness. This was involving very early inhibition of glycogen synthase kinase-3β (GSK-3β), early SNAIL translocation as well as later and long-lasting activation of Wnt/β-catenin-signalling machinery. Experimental manipulation, including silencing of hypoxia-inducible factor (HIF)-1α and the specific inhibition of mitochondrial generation of reactive oxygen species (ROS), revealed that early EMT-related events induced by hypoxia (GSK-3β inhibition and SNAIL translocation) were dependent on transient intracellular increased generation of ROS whereas late migration and invasiveness were sustained by HIF-1α- and vascular endothelial growth factor (VEGF)-dependent mechanisms. These findings indicate that in cancer cells, early redox mechanisms can switch on hypoxia-dependent EMT programme whereas increased invasiveness is sustained by late and HIF-1α-dependent release of VEGF.

Journal Article.  7740 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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