Small molecule-mediated inhibition of Factor VIIa catalytic activity blocks fVIIa:TF cellular signaling and chemokine secretion in human tumor cell lines (original) (raw)

Abstract

In addition to its role in coagulation, Factor VIIa (fVIIa) binding to TF has been demonstrated to activate a variety of intracellular signaling pathways including MAPK, AKT, and Src. This activity has been shown to require TF binding as well as fVIIa protease activity. TF overexpression in tumor epithelial cells and tumor vasculature has been linked to prognosis. However a precise role for fVIIa:TF signaling in tumor cell growth and survival has not yet been established. We have demonstrated that fVIIa is able to activate MAPK, AKT, and early-response gene induction in the BxPC3 pancreatic human tumor cell line at physiologic (0.1-10nM) concentrations. TF expression in the tumor cell line is required for this intracellular signaling. The chemically-inactivated form of fVIIa, fVIIai, is unable to activate these signaling pathways. In addition, preincubation of fVIIa with potent, fVIIa-selective, reversible small molecule inhibitors of fVIIa protease activity inhibited the activation...

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