Journal
EUROPEAN JOURNAL OF CANCER
Volume 45, Issue 3, Pages 454-460Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2008.10.012
Keywords
Protease-activated receptor-1; Hypoxia; Tumour microenvironment; Cell survival; Breast cancer
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Funding
- MIUR [PRIN 2004, PRIN 2007]
- PAR University of Siena [Progetti 2004, Progetti 2006]
- EC-FP6 Integrated Project [I.SHC-CT-2003-503233]
- Ministero della Salute (Prograrnma Integrato Oncologico 2008)
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Aberrant expression of the protease-activated receptor (PAR)-1 has been associated with tumour progression. Indeed, PAR-1 expression correlates with tumour invasiveness, as well as with cancer cell survival. As the tumour microenvironment is characterised by a low oxygen tension, we decided to investigate the role of PAR-1 in cancer cells exposed to a hypoxic microenvironment. in this study we show that hypoxia enhances PAR-1 expression in MDAMB231 breast cancer cells. We next provided evidence for a novel role of PAR-1 in protecting hypoxic breast cancer against cell death, since inhibition of PAR-1 by RNA interference resulted in a decreased cell survival. Finally, we found that treatment of hypoxic MDAMB231 cells with the specific PAR-1 agonist peptide (TRAP) resulted in a significant increase of cell survival and migration. The overall results identify for the first time a functional role for PAR-1 in the cellular responses of breast cancer to a hypoxic microenvironment. (C) 2008 Elsevier Ltd. All rights reserved.
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