Original Articles

Growth Inhibition of MDA-MB-231 Cell Line by Peptides Designed based on uPA

Abstract

Interaction between urokinase-type plasminogen activator (uPA) and its receptor (uPAR) plays an important role in the progression of numerous cancer types including breast cancer by promoting tumor initiating,  proliferation,  invasion  and  metastasis.  Hence,  disruption  of  this  interaction  inhibits  their downstream cascades and subsequently tumor growth. For this, we created two series of 8 and 10 amino acids linear peptides, derived from uPA binding region to target uPAR and studied the inhibition of proliferation in MDA-MB-231 cell line. Results revealed that all of the 10-mer peptides inhibited breast cancer cell proliferation significantly with maximum 40% inhibition of 103 peptides. Meanwhile, none of the 8-mer peptides showed significant toxicity. Current results indicate that the linear 10-mer peptides which mimic a small part of a sequence of a binding domain of uPA to uPAR could be exploited to design a novel class of anti-cancer agents.

Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des 2004;10(1):39-49.

Aref S, El-Sherbiny M, Mabed M, et al. Urokinase plasminogen activator receptor and soluble matrix metalloproteinase-9 in acute myeloid leukemia patients: a possible relation to disease invasion. Hematology 2003;8(6):385-91.

Foekens JA, Peters HA, Look MP, et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res 2000;60(3):636-43.

Meijer-van Gelder ME, Look MP, Peters HA, et al. Urokinase-type plasminogen activator system in breast cancer: association with tamoxifen therapy in recurrent disease. Cancer Res 2004;64(13):4563-8.

Rigolin GM, Tieghi A, Ciccone M, et al. Soluble urokinase-type plasminogen activator receptor (suPAR) as an independent factor predicting worse prognosis and extra-bone marrow involvement in multiple myeloma patients. Br J Haematol 2003;120(6):953-9.

Andreasen PA, Kjoller L, Christensen L, et al. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997;72(1):1-22.

Mazar AP. The urokinase plasminogen activator receptor (uPAR) as a target for the diagnosis and therapy of cancer. Anticancer Drugs 2001;12(5):387-400.

Huai Q, Mazar AP, Kuo A, et al. Structure of human urokinase plasminogen activator in complex with its receptor. Science 2006;311(5761):656-9.

Alfano D, Franco P, Vocca I, et al. The urokinase plasminogen activator and its receptor: role in cell growth and apoptosis. Thromb Haemost 2005;93(2):205-11.

Ploug M. Structure-function relationships in the interaction between the urokinase-type plasminogen activator and its receptor. Curr Pharm Des 2003;9(19):1499-528.

Appella E, Robinson EA, Ullrich SJ, et al. The receptorbinding sequence of urokinase. A biological function for the growth-factor module of proteases. J Biol Chem 1987;262(10):4437-40.

Mazzieri R, Blasi F. The urokinase receptor and the regulation of cell proliferation. Thromb Haemost 2005;93(4):641-6.

Wang Y. The role and regulation of urokinase-type plasminogen activator receptor gene expression in cancer invasion and metastasis. Med Res Rev 2001;21(2):146-70.

Gyetko MR, Todd RF 3rd, Wilkinson CC, et al. The urokinase receptor is required for human monocyte chemotaxis in vitro. J Clin Invest 1994;93(4):1380-7.

Busso N, Nicodeme E, Chesne C, et al. Urokinase and type I plasminogen activator inhibitor production by normal human hepatocytes: modulation by inflammatory agents. Hepatology 1994;20(1 Pt 1):186-90.

Aguirre Ghiso JA, Kovalski K, Ossowski L. Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol 1999;147(1):89-104.

Aguirre Ghiso JA. Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo. Oncogene 2002;21(16):2513-24.

Vial E, Sahai E, Marshall CJ. ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility. Cancer Cell 2003;4(1):67-79.

Liu D, Aguirre Ghiso J, Estrada Y, et al. EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell 2002;1(5):445-57.

Kjoller L, Hall A. Rac mediates cytoskeletal rearrangements and increased cell motility induced by urokinase-type plasminogen activator receptor binding to vitronectin. J Cell Biol 2001;15296):1145-57.

Koshelnick Y, Ehart M, Hufnagl P, et al. Urokinase receptor is associated with the components of the JAK1/STAT1 signaling pathway and leads to activation of this pathway upon receptor clustering in the human kidney epithelial tumor cell line TCL-598, J Biol Chem 1997;272(45):28563-7.

Sidenius N, Blasi F. The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy, Cancer Metastasis Rev 2003;22(2-3):205-22.

Kanse SM, Benzakour O, Kanthou C, et al. Induction of vascular SMC proliferation by urokinase indicates a novel mechanism of action in vasoproliferative disorders. Arterioscler Thromb Vasc Biol 1997;17(11):2848-54.

Tang H, Kerins DM, Hao Q, et al. The urokinase-type plasminogen activator receptor mediates tyrosine phosphorylation of focal adhesion proteins and activation of mitogen-activated protein kinase in cultured endothelial cells. J Biol Chem 1998;273(29):18268-72.

Konakova M, Hucho F, Schleuning WD. Downstream targets of urokinase-type plasminogen-activator-mediated signal transduction. Eur J Biochem 1998;253(2):421-9.

Nguyen DH, Catling AD, Webb DJ, et al. Myosin light chain kinase functions downstream of Ras/ERK to promote migration of urokinase-type plasminogen activator-stimulated cells in an integrin-selective manner. J Cell Biol 1999;146(1):149-64.

Cho SY, Klemke RL. Extracellular-regulated kinase activation and CAS/Crk coupling regulate cell migration and suppress apoptosis during invasion of the extracellular matrix. J Cell Biol 2000;149(1):223-36.

Alfano D, Iaccarino I, Stoppelli MP. Urokinase signaling through its receptor protects against anoikis by increasing BCL-xL expression levels. J Biol Chem 2006;281(26):17758-67.

Lin L, Gardsvoll H, Huai Q, et al. Structure-based engineering of species selectivity in the interaction between urokinase and its receptor: implication for preclinical cancer therapy. J Biol Chem 2010;285(14):10982-92.

Barinka C, Parry G, Callahan J, et al. Structural basis of interaction between urokinase-type plasminogen activator and its receptor. J Mol Biol 2006;363(2):482-95.

Huai Q, Zhou A, Lin L, et al. Crystal structures of two human vitronectin, urokinase and urokinase receptor complexes. Nat Struct Mol Biol 2008;15(4):422-3.

Gardsvoll H, Ploug M. Mapping of the vitronectin-binding site on the urokinase receptor: involvement of a coherent receptor interface consisting of residues from both domain I and the flanking interdomain linker region. J Biol Chem 2007;282(18):13561-72.

Sidenius N, Andolfo A, Fesce R, et al. Urokinase regulates vitronectin binding by controlling urokinase receptor oligomerization. J Biol Chem 2002;277(31):27982-90.

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IssueVol 53, No 7 (2015) QRcode
SectionOriginal Articles
Keywords
uPA uPAR Peptide Growth inhibition Cancer

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How to Cite
1.
Tarighi P, Khorramizadeh MR, Madadkar Sobhani A, Ostad SN, Ghahremani MH. Growth Inhibition of MDA-MB-231 Cell Line by Peptides Designed based on uPA. Acta Med Iran. 2015;53(7):403-407.