Coagulation factors VIIa and Xa inhibit apoptosis and anoikis.
The molecular mechanisms enabling cancer cells to survive loss-of-adhesion-induced apoptosis in the early phases of metastasis remain largely obscure. Interestingly, the overexpression of tissue factor (TF) on tumor cells is associated with successful metastasis and it has now become clear that coagulation factor VIIa (FVIIa), the natural binding partner of TF induces signal transduction in TF-expressing cells. Hence, we investigated the effects of FVIIa-TF interaction on cell survival. We observed that FVIIa, at physiologically relevant concentrations, inhibits cell death and caspase-3 activation induced by serum deprivation and loss of adhesion (lack of integrin signaling) in TF-overexpressing cells, but not in non-TF-expressing cells. This FVIIa effect was not dependent on the formation of the downstream coagulation products FXa or thrombin and was inhibited using an active site-blocked form of FVIIa (FVIIai). FVIIa incubation resulted in the prolonged activation of both the phosphatidylinositide-3-(OH) kinase and p42/p44 MAP kinase pathways, and studies employing pharmacological inhibitors revealed that both the pathways are required for FVIIa-induced cell survival and inhibition of caspase-3 activity. Finally, TF:FVIIa-induced FXa generation dramatically increased cell survival. We propose that FVIIa-induced cell survival may explain why overexpression of TF is associated with successful metastasis.
Versteeg
Henri H
HH
Laboratory for Experimental Internal Medicine, G2-105, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. h.h.versteeg@amc.uva.nl
Spek
C Arnold
CA
Richel
Dick J
DJ
Peppelenbosch
Maikel P
MP
D000818:Animals; D023102:Anoikis / Q000187:drug effects*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D015942:Factor VIIa / Q000494:pharmacology*; D015951:Factor Xa / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt
D053148:Caspase 3; D020169:Caspases; D016895:Culture Media, Serum-Free; D015942:Factor VIIa; D015951:Factor Xa; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt