Identification of a functional role for the protease-activated receptor-1 in hypoxic breast cancer cells.
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.
Naldini
Antonella
A
Department of Physiology, University of Siena, Via Aldo Moro, 53100 Siena, Italy. Naldini@unisi.it
Filippi
Irene
I
Ardinghi
Camilla
C
Silini
Antonietta
A
Giavazzi
Raffaella
R
Carraro
Fabio
F
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D002470:Cell Survival / Q000502:physiology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D044463:Receptor, PAR-1 / Q000378:metabolism*; D018179:Receptors, Thrombin; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D013917:Thrombin