Research Article| Volume 45, ISSUE 3, P454-460, February 2009

Identification of a functional role for the protease-activated receptor-1 in hypoxic breast cancer cells

Published:December 01, 2008DOI:


      Aberrant expression of the protease-activated receptor (PAR)-1 has been associated with tumour progression. Indeed, PAR-1 expression correlates with tumour invasiveness, as well as with cancer cell survival. As the tumour microenvironment is characterised by a low oxygen tension, we decided to investigate the role of PAR-1 in cancer cells exposed to a hypoxic microenvironment. In this study we show that hypoxia enhances PAR-1 expression in MDAMB231 breast cancer cells. We next provided evidence for a novel role of PAR-1 in protecting hypoxic breast cancer against cell death, since inhibition of PAR-1 by RNA interference resulted in a decreased cell survival. Finally, we found that treatment of hypoxic MDAMB231 cells with the specific PAR-1 agonist peptide (TRAP) resulted in a significant increase of cell survival and migration. The overall results identify for the first time a functional role for PAR-1 in the cellular responses of breast cancer to a hypoxic microenvironment.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Chinni C.
        • de Niese M.R.
        • Tew D.J.
        • Jenkins A.L.
        • Bottomley S.P.
        • Mackie E.J.
        Thrombin, a survival factor for cultured myoblasts.
        J Biol Chem. 1999; 274: 9169-9174
        • Goldsack N.R.
        • Chambers R.C.
        • Dabbagh K.
        • Laurent G.J.
        Int J Biochem Cell Biol. 1998; 30: 641-646
        • Bar-Shavit R.
        • Kahn A.
        • Fenton J.W.I.
        • Wilner G.D.
        Chemotactic response of monocytes to thrombin.
        J Cell Biol. 1983; 96: 282-285
        • Sambrano G.R.
        • Coughlin S.R.
        The carboxyl tail of protease-activated receptor-1 is required for chemotaxis.
        Correlation of signal termination and directional migration. J Biol Chem. 1999; 274: 20178-20184
        • Coughlin S.R.
        Thrombin signalling and protease-activated receptors.
        Nature. 2000; 407: 258-264
        • Ossovskaya V.S.
        • Bunnett N.W.
        Protease-activated receptors: contribution to physiology and disease.
        Physiol Rev. 2004; 84: 579-621
        • Massi D.
        • Naldini A.
        • Ardinghi C.
        • et al.
        Expression of protease-activated receptors 1 and 2 in melanocytic nevi and malignant melanoma.
        Hum Pathol. 2005; 36: 676-685
        • Tellez C.
        • Bar-Eli M.
        Role and regulation of the thrombin receptor (PAR-1) in human melanoma.
        Oncogene. 2003; 22: 3130-3137
        • Yin Y.J.
        • Salah Z.
        • Maoz M.
        • et al.
        Oncogenic transformation induces tumor angiogenesis: a role for PAR1 activation.
        FASEB J. 2003; 17: 163-174
        • Kallinowski F.
        • Schlenger K.H.
        • Runkel S.
        • et al.
        Blood flow, metabolism, cellular microenvironment, and growth rate of human tumor xenografts.
        Cancer Res. 1989; 49: 3759-3764
        • Graeber T.G.
        • Osmanian C.
        • Jacks T.
        • et al.
        Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours.
        Nature. 1996; 379: 88-91
        • Yu J.L.
        • Coomber B.L.
        • Kerbel R.S.
        A paradigm for therapy-induced microenvironmental changes in solid tumors leading to drug resistance.
        Differentiation. 2002; 70: 599-609
        • Naldini A.
        • Carney D.H.
        • Pucci A.
        • Carraro F.
        Human alpha-thrombin stimulates proliferation of interferon-gamma differentiated, growth-arrested U937 cells, overcoming differentiation-related changes in expression of p21CIP1/WAF1 and cyclin D1.
        J Cell Physiol. 2002; 191: 290-297
        • Salah Z.
        • Maoz M.
        • Pokroy E.
        • Lotem M.
        • Bar-Shavit R.
        • Uziely B.
        Protease-activated receptor-1 (hPar1), a survival factor eliciting tumor progression.
        Mol Cancer Res. 2007; 5: 229-240
        • Nguyen Q.D.
        • De W.O.
        • Bruyneel E.
        • et al.
        Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho-Rho kinase axis and tumor microenvironment.
        Oncogene. 2005; 24: 8240-8251
        • Minafra S.
        • Morello V.
        • Glorioso F.
        • et al.
        A new cell line (8701-BC) from primary ductal infiltrating carcinoma of human breast.
        Br J Cancer. 1989; 60: 185-192
        • Naldini A.
        • Carraro F.
        Hypoxia modulates cyclin and cytokine expression and inhibits peripheral mononuclear cell proliferation.
        J Cell Physiol. 1999; 181: 448-454
        • Vaupel P.
        • Schlenger K.
        • Knoop C.
        • Höckel M.
        Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements.
        Cancer Res. 1991; 51: 3316-3322
        • Jacobson M.D.
        • Burne J.F.
        • Raff M.C.
        Programmed cell death and Bcl-2 protection in the absence of a nucleus.
        EMBO J. 1994; 13: 1899-1910
        • Naldini A.
        • Bernini C.
        • Pucci A.
        • Carraro F.
        Thrombin-mediated IL-10 up-regulation involves protease-activated receptor (PAR)-1 expression in human mononuclear leukocytes.
        J Leukoc Biol. 2005; 78: 736-744
        • Schioppa T.
        • Uranchimeg B.
        • Saccani A.
        • et al.
        Regulation of the chemokine receptor CXCR4 by hypoxia.
        J Exp Med. 2003; 198: 1391-1402
        • Buccione R.
        • Baldassarre M.
        • Trapani V.
        • et al.
        Glycerophosphoinositols inhibit the ability of tumour cells to invade the extracellular matrix.
        Eur J Cancer. 2005; 41: 470-476
        • Naldini A.
        • Leali D.
        • Pucci A.
        • et al.
        Cutting edge: IL-1beta mediates the proangiogenic activity of osteopontin-activated human monocytes.
        J Immunol. 2006; 177: 4267-4270
        • Vandesompele J.
        • De P.K.
        • Pattyn F.
        • et al.
        Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes.
        Genome Biol. 2002; 3: 1-12
        • Carraro F.
        • Pucci A.
        • Pellegrini M.
        • Pelicci P.G.
        • Baldari C.T.
        • Naldini A.
        P66Shc is involved in promoting HIF-1alpha accumulation and cell death in hypoxic T cells.
        J Cell Physiol. 2007; 211: 439-447
        • Boire A.
        • Covic L.
        • Agarwal A.
        • Jacques S.
        • Sherifi S.
        • Kuliopulos A.
        PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells.
        Cell. 2005; 120: 303-313
        • Kataoka H.
        • Hamilton J.R.
        • McKemy D.D.
        • et al.
        Protease-activated receptors 1 and 4 mediate thrombin signaling in endothelial cells.
        Blood. 2003; 102: 3224-3231
        • Maulon L.
        • Guérin S.
        • Ricci J.-.E.
        • Farahifar D.
        • Breittmayer J.-.P.
        • Auberger P.
        T-cell receptor signaling pathway exerts a negative control on thrombin-mediated increase in [Ca2+]i and p38 MAPK activation in Jurkat T cells: implication of the tyrosine kinase p56Lck.
        Blood. 1998; 91: 4232-4241
        • Huang C.
        • Jacobson K.
        • Schaller M.D.
        MAP kinases and cell migration.
        J Cell Sci. 2004; 117: 4619-4628
        • Page E.L.
        • Robitaille G.A.
        • Pouyssegur J.
        • Richard D.E.
        Induction of hypoxia-inducible factor-1alpha by transcriptional and translational mechanisms.
        J Biol Chem. 2002; 277: 48403-48409
        • Chalmers C.J.
        • Balmanno K.
        • Hadfield K.
        • Ley R.
        • Cook S.J.
        Thrombin inhibits Bim (Bcl-2-interacting mediator of cell death) expression and prevents serum-withdrawal-induced apoptosis via protease-activated receptor 1.
        Biochem J. 2003; 375: 99-109
        • Yin Y.J.
        • Katz V.
        • Salah Z.
        • et al.
        Mammary Gland Tissue Targeted Overexpression of Human Protease-Activated Receptor 1 Reveals a Novel Link to {beta}-Catenin Stabilization.
        Cancer Res. 2006; 66: 5224-5233
        • Shin I.
        • Kim S.
        • Song H.
        • Kim H.R.
        • Moon A.
        H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells.
        J Biol Chem. 2005; 280: 14675-14683