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Thromb Haemost 2008; 100(01): 127-133
DOI: 10.1160/TH07-12-0722
Cellular Proteolysis and Oncology
Schattauer GmbH

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

Xiaofeng Jiang
1   Sol Sherry Thrombosis Research Center
,
Shimei Zhu
2   Department of Anatomy, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
,
Tracee S. Panetti
1   Sol Sherry Thrombosis Research Center
,
Michael E. Bromberg
1   Sol Sherry Thrombosis Research Center
› Author AffiliationsFinancial support: Supported by grants from WW Smith Charitable Trust (MEB) and BC033382, Department of the U.S. Army (MEB).
Further Information

Publication History

Received 06 December 2007

Accepted after major revision 14 May 2008

Publication Date:
22 November 2017 (online)

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Summary

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 thatTFFVIIa-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 TFFVIIa-FXa complex. These studies suggest thatTFFVIIa-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.

Keywords

Tissue factor - factor VIIa - factor Xa - mammalian target of rapamycin - breast cancer
 

  • References

  • 1 Nemerson Y. Tissue factor and hemostasis. Blood 1988; 71: 1-8.
    PubMedGoogle Scholar
  • 2 Poulsen LK, Jacobsen N, Sorensen BB. et al. Signal transduction via the mitogen-activated protein kinase pathway induced by binding of coagulation factor VIIa to tissue factor. J Biol Chem 1998; 273: 6228-6232.
    CrossrefPubMedGoogle Scholar
  • 3 Verteeg HH, Hoedemaeker I, Diks SH. et al. Factor VIIa/tissue factor-induced signaling via Src-like kinases, phosphatidylinositol 3-kinase, and Rac. J Biol Chem 2000; 275: 28750-28756.
    CrossrefPubMedGoogle Scholar
  • 4 Sorensen BB, Rao LV, Tornehave D. et al. Antiapop-totic effect of coagulation factor VIIa. Blood 2003; 102: 1708-1715.
    CrossrefPubMedGoogle Scholar
  • 5 Rao LV, Pendurthi UR. Tissue factor-factor VIIa signaling. Arterioscler Thromb Va sc Biol 2005; 25: 47-56.
    PubMedGoogle Scholar
  • 6 Hjortoe GM, Petersen LC, Albrektsen T. et al. Tissue factor-factor VIIa-specific up-regulation of IL-8 expression in MDA-MB-231 cells is mediated by PA R-2 and results in increased cell migration. Blood 2004; 103: 3029-3037.
    CrossrefPubMedGoogle Scholar
  • 7 Camerer E, Rottingen JA, Gjernes E. et al. Coagulation factors VIIa and Xa induce cell signaling leading to up-regulation of the egr-1 gene. J Biol Chem 1999; 274: 32225-32233.
    CrossrefPubMedGoogle Scholar
  • 8 Pendurthi UR, Allen KE, Ezban M. et al. Factor VIIa and thrombin induce the expression of Cyr61 and connective tissue growth factor, extracellular matrix signaling proteins that could act as possible downstream mediators in factor VIIa.tissue factor-induced signal transduction. J Biol Chem 2000; 275: 14632-14641.
    CrossrefPubMedGoogle Scholar
  • 9 Jiang X, Bailly MA, Panetti TS. et al. Formation of tissue factor-factor VIIa-factor Xa complex promotes cellular signaling and migration of human breast cancer cells. J Thromb Haemost 2004; 02: 93-101.
    CrossrefPubMedGoogle Scholar
  • 10 Morris DR, Ding Y, Ricks TK. et al. Protease-activated receptor-2 is essential for factor VIIa and Xa-in-duced signaling, migration, and invasion of breast cancer cells. Cancer Res 2006; 66: 307-314.
    CrossrefPubMedGoogle Scholar
  • 11 Jiang X, Guo YL, Bromberg ME. Formation of tissue factor: Factor VIIa-factor Xa complex prevents apoptosis in human breast cancer cells. Thromb Haemost 2006; 96: 196-201.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Versteeg HH, Sorensen BB, Slofstra SH. et al. VIIa/ tissue factor interaction results in a tissue factor cytoplasmic domain-independent activation of protein synthesis, p70, and p90 S6 kinase phosphorylation. J Biol Chem 2002; 277: 27065-27072.
    CrossrefPubMedGoogle Scholar
  • 13 Camerer E, Huang W, Coughlin SR. Tissue factor-and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci USA 2000; 97: 5255-5260.
    CrossrefPubMedGoogle Scholar
  • 14 Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med 2005; 11: 353-361.
    CrossrefPubMedGoogle Scholar
  • 15 Sarbassov dos D, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005; 17: 596-603.
    CrossrefPubMedGoogle Scholar
  • 16 Loewith R, Jacinto E, Wullschleger S. et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 2002; 10: 457-468.
    CrossrefPubMedGoogle Scholar
  • 17 Sarbassov DD, Ali SM, Kim DH. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14: 1296-1302.
    CrossrefPubMedGoogle Scholar
  • 18 Yang Q, Guan KL. Expanding mTOR signaling. Cell Res 2007; 17: 666-681.
    CrossrefPubMedGoogle Scholar
  • 19 Jacinto E, Loewith R, Schmidt A. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 06: 1122-1128.
    CrossrefPubMedGoogle Scholar
  • 20 Sarbassov DD, Ali SM, Sengupta S. et al. Prolonged rapamycin treatment inhibits mTORC2 assemby and Akt/PKB Mol Cell. 2006; 22: 159-168.
    PubMedGoogle Scholar
  • 21 Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004; 04: 335-348.
    CrossrefPubMedGoogle Scholar
  • 22 Hynes NE, Boulay A. The mTOR pathway in breast cancer. J Mammary Gland Biol Neoplasia 2006; 11: 53-61.
    CrossrefPubMedGoogle Scholar
  • 23 Morrissey JH, Fair DS, Edgington TS. Monoclonal antibody analysis of purified and cellassociated tissue factor. Thromb Res 1988; 52: 247-261.
    CrossrefPubMedGoogle Scholar
  • 24 Dufner A, Thomas G. Ribosomal S6 kinas signaling and the control of translation. Exp Cell Res 1999; 253: 100-109.
    CrossrefPubMedGoogle Scholar
  • 25 Poon M, Marx SO, Gallo R. et al. Rapamycin inhibits vascular smooth muscle cell migration. J Clin Invest 1996; 98: 2277-2283.
    CrossrefPubMedGoogle Scholar
  • 26 Sakakibra K, Liu B, Hollenbeck S. et al. Rapamycin inhibits fibronectin-induced migration of the human arterial smooth muscle line (E47) through the mammalian target of rapamycin. Am J Physiol Heart Circ Physiol 2005; 288: H2861-H2868.
    CrossrefPubMedGoogle Scholar
  • 27 Ueno T, Toi M, Koike M. et al. Tissue factor expression in breast cancer tissues: its correlation with prognosis and plasma concentration. Br J Cancer 2000; 83: 164-170.
    CrossrefPubMedGoogle Scholar
  • 28 Noh WC, Kim YH, Kim MS. et al. Activation of the mTOR signaling pathway in breast cancer and its correlation with the clinicopathologic variables. Breast Cancer Res Treat. 2008 in press.
    PubMedGoogle Scholar
  • 29 Lin HJ, Hsieh FC, Song H. et al. Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer. Br J Cancer 2005; 93: 1372-1381.
    CrossrefPubMedGoogle Scholar
  • 30 Riewald M, Ruf W. Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor. Proc Natl Acad Sci USA 2001; 98: 7742-7747.
    CrossrefPubMedGoogle Scholar
  • 31 Kamath L, Meydani A, Foss F. et al. Signaling from protease-activated receptor-1 inhibits migration and invasion of breast cancer cells. Cancer Res 2001; 61: 5933-5940.
    PubMedGoogle Scholar
  • 32 Qiu Q, Yang M, Tsang BK. et al. Both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signalling are required in epidermal growth factor-induced human trophoblast migration. Mol Hum Reprod 2004; 10: 677-684.
    CrossrefPubMedGoogle Scholar
  • 33 Berven LA, Willard FS, Crouch MF. Role of the p70(S6K) pathway in regulating the actin cytoskeleton and cell migration. Exp Cell Res 2004; 296: 183-195.
    CrossrefPubMedGoogle Scholar
  • 34 Qian Y, Corum L, Meng Q. et al. PI3K induced actin filament remodeling through Akt and p70S6K1: implication of essential role in cell migration. Am J Physiol Cell Physiol 2004; 286: C153-163.
    CrossrefPubMedGoogle Scholar
  • 35 Chan S, Scheulen ME, Johnson S. et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 2005; 23: 5314-5322.
    CrossrefPubMedGoogle Scholar