Coagulation factor Xa inhibits cancer cell migration via protease-activated receptor-1 activation.
Cell migration is critically important in (patho)physiological processes. The metastatic potential of cancer cells partly depends on activation of the coagulation cascade. The aim of the present study was to determine whether coagulation factor X (FXa) can regulate the migration and invasion of cancer cells. Quite unexpectedly, we found that FXa markedly diminished the migration of different cancer cell lines of various origins (breast, lung and colon cancer cells). We showed that FXa mediated inhibition of cancer cell migration was specific, as it was inhibited by TAP (a specific FXa inhibitor) but not by Hirudin (a specific thrombin inhibitor). Moreover, the FXa effect was dose dependent, with a maximal inhibitory effect reached at 0.75 U/ml FXa (corresponding to 130.5 nM). Next, we determined that FXa acted via protease-activated receptor (PAR)-1-dependent signaling, and PAR-1 desensitization, as well as knocking-down PAR-1 expression, abolished the FXa effects. Finally, we showed that Gialpha was not involved in FXa mediated inhibition of cell migration as its effects were not reverted by pertussis toxin. These results suggest that, beyond its role in blood coagulation, FXa plays a key role in cancer cell migration. They also shed light on an unexpected role of PAR-1, which appears to be a Janus-like receptor in cancer cell biology.
Borensztajn
Keren
K
Department of Cell Biology, University of Groningen, Groningen, The Netherlands. K.S.Borensztajn@amc.uva.nl
Bijlsma
Maarten F
MF
Reitsma
Pieter H
PH
Peppelenbosch
Maikel P
MP
Spek
C Arnold
CA
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015951:Factor Xa / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D045325:HCT116 Cells / Q000378:metabolism / Q000473:pathology; D019073:HT29 Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism*; D014162:Transfection
D034741:RNA, Small Interfering; D044463:Receptor, PAR-1; D015951:Factor Xa