Formation of tissue factor-factor VIIa-factor Xa complex induces activation of the mTOR pathway which regulates migration of human breast cancer cells

• Published in: Thrombosis and haemostasis Vol. 100; no. 1; p. 127
• Main Authors: Jiang, Xiaofeng, Zhu, Shimei, Panetti, Tracee S, Bromberg, Michael E
• Format: Journal Article
• Language: English
• Published: Germany 01.07.2008
• Subjects: Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Movement - drug effects; Chromones - pharmacology; Factor VIIa - metabolism; Factor Xa - metabolism; Female; Humans; Morpholines - pharmacology; Neoplasm Invasiveness; Peptides - pharmacology; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein Kinases - drug effects; Protein Kinases - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Receptor, PAR-1 - metabolism; Receptor, PAR-2 - metabolism; Recombinant Proteins - metabolism; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Sirolimus - pharmacology; Thromboplastin - metabolism; TOR Serine-Threonine Kinases
• ISSN: 0340-6245
• DOI: 10.1160/TH07-12-0722

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 that TF-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.