Formation of tissue factor-factor VIIa-factor Xa complex induces activation of the mTOR pathway which regulates migration of human breast cancer cells
Xiaofeng Jiang1, Shimei Zhu2, Tracee S. Panetti1, Michael E. Bromberg1
1Sol Sherry Thrombosis Research Center, 2Department of Anatomy, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
breast cancer, Tissue factor, factor Xa, factorVIIa, mammalian target of rapamycin
Tissue factor (TF) is a transmembrane glycoprotein that initiates blood coagulation when complexed with activated factor VII (FVIIa).TF is constitutively expressed in a variety of tumor cells and has been implicated in cellular signaling, angiogenesis, and tumor progression. Formation of TF-FVIIa complex and generation of downstream coagulation proteases, including activated factor X (FXa) and thrombin, initiate signaling by activation of protease-activated receptors (PARs).We have previously shown thatTF-FVIIa-Xa complex formation promotes phosphorylation of p44/42 mitogen-activated protein kinase and Akt/protein kinase B in human breast cancer cells. In the present study, we show that formation of TF-FVIIa-FXa complex induces phosphorylation of mammalian target of rapamycin (mTOR) and p70 S6 kinase in a human breast cancer cell line, Adr-MCF-7. Activation of the mTOR pathway, which is probably mediated by PAR1 and/or PAR2, was associated with enhanced cell migration, a key step in the metastatic cascade. Inhibition of this pathway with the specific mTOR inhibitor, rapamycin, markedly decreased cell migration induced by formation of TF-FVIIa-FXa complex.These studies suggest that TF-FVIIa-mediated signaling modulates mTOR pathway activation, which regulates in part breast cancer cell migration.Targeting the TF-mediated cell signaling pathway might represent a novel strategy for the treatment of breast cancer.