Overexpression of tissue factor in cancer cells inhibits chemotherapy-induced apoptosis by activating Bcl-2 expression through the JAK/STAT5 pathway

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Tissue factor (TF) is a transmembrane protein that acts as a receptor for activated coagulation factor VII (FVIIa), initiating the coagulation cascade. Recent studies demonstrate that expression of tumor-derived TF also mediates intracellular signaling relevant to tumor growth and metastasis. Our present study reports that overexpression of TF in cancer cells acts to upregulate Bcl-2 expression via the JAK/STAT5 pathway, resulting in enhanced cell survival and resistance to chemotherapeutic drug-induced apoptosis. Inhibition of endogenous TF expression in TF-overexpressing cancer cells using siRNA resulted in decreased cell growth and sensitization to doxorubicin-induced apoptosis. In contrast, enforced expression of TF in TF-negative cancer cells in the presence of FVIIa was found to induce upregulation of Bcl-2, leading to resistance to doxorubicin. Additionally, cancer cells expressing high levels of either endogenous or transfected TF treated with FVIIa readily activated STAT5 and Akt. Using selective pharmacologic inhibitors, we demonstrated that JAK inhibitor I, but not the PI3K inhibitor LY294002, blocked the TF/FVIIa-induced upregulation of Bcl-2. These results suggest that overexpression of TF by tumor cells ligated with FVIIa upregulate Bcl-2 expression through the JAK/STAT5 signaling pathway, resulting in resistance to apoptosis. This activity may contribute, at least in part, to tumor development and progression.