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Carcinogenesis Advance Access published online on September 12, 2008
Carcinogenesis, doi:10.1093/carcin/bgn216
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Dip. Medicina e Oncologia Sperimentale and Centro Interuniversitario di Fisiopatologia Epatica, University of Torino, Italy

Corresponding Author Prof. Maurizio Parola, Dip. Medicina e Oncologia Sperimentale, Università degli Studi di Torino, Corso Raffaello 30, 10125 Torino, Italy, Phone +39-011-6707772, Fax +39-011-6707753, e-mail maurizio.parola{at}unito.it

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 program as well as to mechanistically elucidate signal transduction mechanisms involved.

The following human cancer cell lines were used: HepG2 (from human hepatoblastoma), Panc1 (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 hrs by classic EMT changes (fibroblastoid phenotype, SNAIL and β-catenin nuclear translocation, changes in E-cadherin) and by increased migration and invasiveness. This was involving very early inhibition of GSK-3β, early SNAIL translocation as well as later and long-lasting activation of Wnt/β-catenin signalling machinery. Experimental manipulation, including silencing of HIF1{alpha} 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 HIF1{alpha} - and VEGF -dependent mechanisms.

These findings indicate that in cancer cells early redox mechanisms can switch-on hypoxia - dependent EMT program whereas increased invasiveness is sustained by late and HIF-1{alpha} - dependent release of VEGF.

Key Words: Epithelial – mesenchymal transition • hypoxia • epithelial tumour cells • wnt/β-catenin signalling • reactive oxygen species • HIF-1{alpha} • VEGF

Received May 30, 2008; revised September 1, 2008; accepted September 6, 2008.


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