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Coagulation factor Xa inhibits cancer cell migration via protease-activated receptor-1 activation
Keren Borensztajn1, Maarten F Bijlsma, Pieter H Reitsma
1Department of Cell Biology, University of Groningen, Groningen, The Netherlands. K.S.Borensztajn@amc.uva.nl
Abstract:
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.
Insights
Coagulation factor Xa (FXa) unexpectedly inhibits cancer cell migration and invasion. This FXa-mediated effect is specific, dose-dependent, and acts via protease-activated receptor-1 (PAR-1) signaling.
Area of Science:
- Biochemistry
- Oncology
- Cell Biology
Background:
- Cell migration is crucial for physiological and pathological processes.
- Cancer cell metastasis is linked to the coagulation cascade.
- The role of coagulation factor Xa (FXa) in cancer cell migration is not well understood.
Purpose of the Study:
- To investigate the effect of FXa on cancer cell migration and invasion.
- To elucidate the signaling pathways involved in FXa-mediated regulation of cancer cell motility.
Main Methods:
- Testing FXa on various cancer cell lines (breast, lung, colon).
- Utilizing specific FXa and thrombin inhibitors (TAP, Hirudin).
- Investigating FXa signaling via protease-activated receptor-1 (PAR-1) and G-alpha subunits.
Main Results:
- FXa significantly reduced migration and invasion in breast, lung, and colon cancer cells.
- The inhibitory effect was specific to FXa and dose-dependent.
- FXa's action was mediated by PAR-1 signaling, independent of G-alpha subunits.
Conclusions:
- FXa plays a significant, inhibitory role in cancer cell migration beyond its coagulation function.
- PAR-1 acts as a key mediator in FXa's regulation of cancer cell motility, exhibiting a dual role in cancer biology.
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