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Epsilon-aminocaproic acid prevents high glucose and insulin induced-invasiveness in MDA-MB-231 breast cancer cells, modulating the plasminogen activator system

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Abstract

Obesity and type II diabetes mellitus have contributed to the increase of breast cancer incidence worldwide. High glucose concentration promotes the proliferation of metastatic cells, favoring the activation of the plasminogen/plasmin system, thus contributing to tumor progression. The efficient formation of plasmin is dependent on the binding of plasminogen to the cell surface. We studied the effect of ε-aminocaproic acid (EACA), an inhibitor of the binding of plasminogen to cell surface, on proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and plasminogen activation system, in metastatic MDA-MB-231 breast cancer cells grown in a high glucose microenvironment and treated with insulin. MDA-MB-231 cells were treated with EACA 12.5 mmol/L under high glucose 30 mmol/L (HG) and high glucose and insulin 80 nmol/L (HG-I) conditions, evaluating: cell population growth, % of viability, migratory, and invasive abilities, as well as the expression of uPA, its receptor (uPAR), and its inhibitor (PAI-1), by real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, MMP-2 and MMP-9 mRNAs were evaluated by RT-PCR. Markers of EMT were evaluated by Western blot. Additionally, the presence of active uPA was studied by gel zymography, using casein-plasminogen as substrates. EACA prevented the increase in cell population, migration and invasion induced by HG and insulin, which was associated with the inhibition of EMT and the attenuation of HG- and insulin-dependent expression of uPA, uPAR, PAI-1, MMP-2, MMP-9, α-enolase (ENO A), and HCAM. The interaction of plasminogen to the cell surface and plasmin formation are mediators of the prometastasic action of hyperglycemia and insulin, potentially, EACA can be employed in the prevention and as adjuvant treatment of breast tumorigenesis promoted by hyperglycemia and insulin.

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References

  1. Peairs KS, Barone BB, Snyder CF, Yeh HC, Stein KB, Derr RL, Brancati FL, Wolff AC (2011) Diabetes mellitus and breast cancer outcomes: a systematic review and meta-analysis. J Clin Oncol 29:40–46. doi:10.1200/JCO.2009.27.3011

    Article  PubMed  Google Scholar 

  2. Takatani-Nakase T, Matsui C, Maeda S, Kawahara S, Takahashi K (2014) High glucose level promotes migration behavior of breast cancer cells through zinc and its transporters. PLoS ONE 9:e90136. doi:10.1371/journal.pone.0090136

    Article  PubMed  PubMed Central  Google Scholar 

  3. Westley RL, May FE (2013) A twenty-first century cancer epidemic caused by obesity: the involvement of insulin, diabetes, and insulin-like growth factors. Int J Endocrinol 2013:632461. doi:10.1155/2013/632461

    Article  PubMed  PubMed Central  Google Scholar 

  4. Zhu S, Yao F, Li WH, Wan JN, Zhang YM, Tang Z, Khan S, Wang CH, Sun SR (2013) PKC?-dependent activation of the ubiquitin proteasome system is responsible for high glucose-induced human breast cancer MCF-7 cell proliferation, migration and invasion. Asian Pac J Cancer Prev 14:5687–5692

    Article  PubMed  Google Scholar 

  5. Altenberg B, Greulich KO (2004) Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics 84:1014–1020. doi:10.1016/j.ygeno.2004.08.010

    Article  CAS  PubMed  Google Scholar 

  6. Zordoky BN, Bark D, Soltys CL, Sung MM, Dyck JR (2014) The anti-proliferative effect of metformin in triple-negative MDA-MB-231 breast cancer cells is highly dependent on glucose concentration: implications for cancer therapy and prevention. Biochim Biophys Acta 1840:1943–1957. doi:10.1016/j.bbagen.2014.01.023

    Article  CAS  PubMed  Google Scholar 

  7. Wahdan-Alaswad R, Fan Z, Edgerton SM, Liu B, Deng XS, Arnadottir SS, Richer JK, Anderson SM, Thor AD (2013) Glucose promotes breast cancer aggression and reduces metformin efficacy. Cell Cycle 12:3759–3769. doi:10.4161/cc.26641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yamamoto M, Patel NA, Taggart J, Sridhar R, Cooper DR (1999) A shift from normal to high glucose levels stimulates cell proliferation in drug sensitive MCF-7 human breast cancer cells but not in multidrug resistant MCF-7/ADR cells which overproduce PKC-betaII. Int J Cancer 83:98–106

    Article  CAS  PubMed  Google Scholar 

  9. Okumura M, Yamamoto M, Sakuma H, Kojima T, Maruyama T, Jamali M, Cooper DR, Yasuda K (2002) Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: reciprocal involvement of PKC-alpha and PPAR expression. Biochim Biophys Acta 1592:107–116

    Article  CAS  PubMed  Google Scholar 

  10. Rose DP, Vona-Davis L (2012) The cellular and molecular mechanisms by which insulin influences breast cancer risk and progression. Endocr Relat Cancer 19:R225–R241. doi:10.1530/ERC-12-0203

    Article  CAS  PubMed  Google Scholar 

  11. Hajjar KA, Harpel PC, Jaffe EA, Nachman RL (1986) Binding of plasminogen to cultured human endothelial cells. J Biol Chem 261:11656–11662

    CAS  PubMed  Google Scholar 

  12. Irigoyen JP, Munoz-Canoves P, Montero L, Koziczak M, Nagamine Y (1999) The plasminogen activator system: biology and regulation. Cell Mol Life Sci 56:104–132

    Article  CAS  PubMed  Google Scholar 

  13. Kumari S, Malla R (2015) New insight on the role of plasminogen receptor in cancer progression. Cancer Growth Metastasis 8:35–42. doi:10.4137/CGM.S27335

    Article  PubMed  PubMed Central  Google Scholar 

  14. Burtin P, Zhang S, Schauffler J, Komano O, Sastre X, Mathieu MC (1993) Visualization of the plasmin receptor on sections of human mammary carcinoma cells. Int J Cancer 53:17–21

    Article  CAS  PubMed  Google Scholar 

  15. Ranson M, Andronicos NM, O’Mullane MJ, Baker MS (1998) Increased plasminogen binding is associated with metastatic breast cancer cells: differential expression of plasminogen binding proteins. Br J Cancer 77:1586–1597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stillfried GE, Saunders DN, Ranson M (2007) Plasminogen binding and activation at the breast cancer cell surface: the integral role of urokinase activity. Breast Cancer Res 9:R14. doi:10.1186/bcr1647

    Article  PubMed  PubMed Central  Google Scholar 

  17. Plow EF, Doeuvre L, Das R (2012) So many plasminogen receptors: why? J Biomed Biotechnol 2012:141806. doi:10.1155/2012/141806

    Article  PubMed  PubMed Central  Google Scholar 

  18. Almholt K, Juncker-Jensen A, Laerum OD, Johnsen M, Romer J, Lund LR (2013) Spontaneous metastasis in congenic mice with transgenic breast cancer is unaffected by plasminogen gene ablation. Clin Exp Metastasis 30:277–288. doi:10.1007/s10585-012-9534-9

    Article  CAS  PubMed  Google Scholar 

  19. Capello M, Ferri-Borgogno S, Cappello P, Novelli F (2011) alpha-Enolase: a promising therapeutic and diagnostic tumor target. FEBS J 278:1064–1074. doi:10.1111/j.1742-4658.2011.08025.x

    Article  CAS  PubMed  Google Scholar 

  20. Tu SH, Chang CC, Chen CS, Tam KW, Wang YJ, Lee CH, Lin HW, Cheng TC, Huang CS, Chu JS, Shih NY, Chen LC, Leu SJ, Ho YS, Wu CH (2010) Increased expression of enolase alpha in human breast cancer confers tamoxifen resistance in human breast cancer cells. Breast Cancer Res Treat 121:539–553. doi:10.1007/s10549-009-0492-0

    Article  CAS  PubMed  Google Scholar 

  21. Shih NY, Lai HL, Chang GC, Lin HC, Wu YC, Liu JM, Liu KJ, Tseng SW (2010) Anti-alpha-enolase autoantibodies are down-regulated in advanced cancer patients. Jpn J Clin Oncol 40:663–669. doi:10.1093/jjco/hyq028

    Article  PubMed  Google Scholar 

  22. Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M (2005) In vitro and in vivo antitumorigenic activity of a mixture of lysine, proline, ascorbic acid, and green tea extract on human breast cancer lines MDA-MB-231 and MCF-7. Med Oncol 22:129–138. doi:10.1385/MO:22:2:129

    Article  CAS  PubMed  Google Scholar 

  23. Makwana J, Paranjape S, Goswami J (2010) Antifibrinolytics in liver surgery. Indian J Anaesth 54:489–495. doi:10.4103/0019-5049.72636

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sun Z, Chen YH, Wang P, Zhang J, Gurewich V, Zhang P, Liu JN (2002) The blockage of the high-affinity lysine binding sites of plasminogen by EACA significantly inhibits prourokinase-induced plasminogen activation. Biochim Biophys Acta 1596:182–192

    Article  CAS  PubMed  Google Scholar 

  25. Li W, Ma Q, Li J, Guo K, Liu H, Han L, Ma G (2011) Hyperglycemia enhances the invasive and migratory activity of pancreatic cancer cells via hydrogen peroxide. Oncol Rep 25:1279–1287. doi:10.3892/or.2011.1150

    CAS  PubMed  Google Scholar 

  26. Saengboonmee C, Seubwai W, Pairojkul C, Wongkham S (2016) High glucose enhances progression of cholangiocarcinoma cells via STAT3 activation. Sci Rep 6:18995. doi:10.1038/srep18995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Flores-Lopez LA, Martinez-Hernandez MG, Viedma-Rodriguez R, Diaz-Flores M, Baiza-Gutman LA (2016) High glucose and insulin enhance uPA expression, ROS formation and invasiveness in breast cancer-derived cells. Cell Oncol (Dordr) 39:365–378. doi:10.1007/s13402-016-0282-8

    Article  CAS  Google Scholar 

  28. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  PubMed  Google Scholar 

  29. Sumantran VN (2011) Cellular chemosensitivity assays: an overview. Methods Mol Biol 731:219–236. doi:10.1007/978-1-61779-080-5_19

    Article  CAS  PubMed  Google Scholar 

  30. Watanabe T, Miura T, Degawa Y, Fujita Y, Inoue M, Kawaguchi M, Furihata C (2010) Comparison of lung cancer cell lines representing four histopathological subtypes with gene expression profiling using quantitative real-time PCR. Cancer Cell Int 10:2. doi:10.1186/1475-2867-10-2

    Article  PubMed  PubMed Central  Google Scholar 

  31. Gregory KJ, Zhao B, Bielenberg DR, Dridi S, Wu J, Jiang W, Huang B, Pirie-Shepherd S, Fannon M (2010) Vitamin D binding protein-macrophage activating factor directly inhibits proliferation, migration, and uPAR expression of prostate cancer cells. PLoS ONE 5:e13428. doi:10.1371/journal.pone.0013428

    Article  PubMed  PubMed Central  Google Scholar 

  32. Meade ES, Ma YY, Guller S (2007) Role of hypoxia-inducible transcription factors 1alpha and 2alpha in the regulation of plasminogen activator inhibitor-1 expression in a human trophoblast cell line. Placenta 28:1012–1019. doi:10.1016/j.placenta.2007.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yoon JJ, Lee YJ, Kim JS, Kang DG, Lee HS (2010) Betulinic acid inhibits high glucose-induced vascular smooth muscle cells proliferation and migration. J Cell Biochem 111:1501–1511. doi:10.1002/jcb.22880

    Article  CAS  PubMed  Google Scholar 

  34. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  CAS  PubMed  Google Scholar 

  35. Legrand C, Polette M, Tournier JM, de Bentzmann S, Huet E, Monteau M, Birembaut P (2001) uPA/plasmin system-mediated MMP-9 activation is implicated in bronchial epithelial cell migration. Exp Cell Res 264:326–336. doi:10.1006/excr.2000.5125

    Article  CAS  PubMed  Google Scholar 

  36. Larue L, Bellacosa A (2005) Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene 24:7443–7454. doi:10.1038/sj.onc.1209091

    Article  CAS  PubMed  Google Scholar 

  37. Singhai R, Patil VW, Jaiswal SR, Patil SD, Tayade MB, Patil AV (2011) E-Cadherin as a diagnostic biomarker in breast cancer. N Am J Med Sci 3:227–233. doi:10.4297/najms.2011.3227

    Article  PubMed  PubMed Central  Google Scholar 

  38. Uchino M, Kojima H, Wada K, Imada M, Onoda F, Satofuka H, Utsugi T, Murakami Y (2010) Nuclear beta-catenin and CD44 upregulation characterize invasive cell populations in non-aggressive MCF-7 breast cancer cells. BMC Cancer 10:414. doi:10.1186/1471-2407-10-414

    Article  PubMed  PubMed Central  Google Scholar 

  39. Montuori N, Salzano S, Rossi G, Ragno P (2000) Urokinase-type plasminogen activator up-regulates the expression of its cellular receptor. FEBS Lett 476:166–170

    Article  CAS  PubMed  Google Scholar 

  40. Liu Y, Shetty AC, Schwartz JA, Bradford LL, Xu W, Phan QT, Kumari P, Mahurkar A, Mitchell AP, Ravel J, Fraser CM, Filler SG, Bruno VM (2015) New signaling pathways govern the host response to C. albicans infection in various niches. Genome Res 25:679–689. doi:10.1101/gr.187427.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Han B, Nakamura M, Mori I, Nakamura Y, Kakudo K (2005) Urokinase-type plasminogen activator system and breast cancer (Review). Oncol Rep 14:105–112

    CAS  PubMed  Google Scholar 

  42. Ceruti P, Principe M, Capello M, Cappello P, Novelli F (2013) Three are better than one: plasminogen receptors as cancer theranostic targets. Exp Hematol Oncol 2:12. doi:10.1186/2162-3619-2-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sharma M, Blackman MR, Sharma MC (2012) Antibody-directed neutralization of annexin II (ANX II) inhibits neoangiogenesis and human breast tumor growth in a xenograft model. Exp Mol Pathol 92:175–184. doi:10.1016/j.yexmp.2011.10.003

    Article  CAS  PubMed  Google Scholar 

  44. Sharma A, Paranjape AN, Rangarajan A, Dighe RR (2012) A monoclonal antibody against human Notch1 ligand-binding domain depletes subpopulation of putative breast cancer stem-like cells. Mol Cancer Ther 11:77–86. doi:10.1158/1535-7163.MCT-11-0508

    Article  CAS  PubMed  Google Scholar 

  45. Diaz-Ramos A, Roig-Borrellas A, Garcia-Melero A, Lopez-Alemany R (2012) alpha-Enolase, a multifunctional protein: its role on pathophysiological situations. J Biomed Biotechnol 2012:156795. doi:10.1155/2012/156795

    Article  PubMed  PubMed Central  Google Scholar 

  46. Lopez-Alemany R, Correc P, Camoin L, Burtin P (1994) Purification of the plasmin receptor from human carcinoma cells and comparison to alpha-enolase. Thromb Res 75:371–381

    Article  CAS  PubMed  Google Scholar 

  47. Hsiao KC, Shih NY, Fang HL, Huang TS, Kuo CC, Chu PY, Hung YM, Chou SW, Yang YY, Chang GC, Liu KJ (2013) Surface alpha-enolase promotes extracellular matrix degradation and tumor metastasis and represents a new therapeutic target. PLoS ONE 8:e69354. doi:10.1371/journal.pone.0069354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hembrough TA, Li L, Gonias SL (1996) Cell-surface cytokeratin 8 is the major plasminogen receptor on breast cancer cells and is required for the accelerated activation of cell-associated plasminogen by tissue-type plasminogen activator. J Biol Chem 271:25684–25691

    Article  CAS  PubMed  Google Scholar 

  49. Herren T, Burke TA, Das R, Plow EF (2006) Identification of histone H2B as a regulated plasminogen receptor. Biochemistry 45:9463–9474. doi:10.1021/bi060756w

    Article  CAS  PubMed  Google Scholar 

  50. Andronicos NM, Chen EI, Baik N, Bai H, Parmer CM, Kiosses WB, Kamps MP, Yates JR 3rd, Parmer RJ, Miles LA (2010) Proteomics-based discovery of a novel, structurally unique, and developmentally regulated plasminogen receptor, Plg-RKT, a major regulator of cell surface plasminogen activation. Blood 115:1319–1330. doi:10.1182/blood-2008-11-188938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ueshima S, Okada K, Matsuo O (1996) Stabilization of plasmin by lysine derivatives. Clin Chim Acta 245:7–18

    Article  CAS  PubMed  Google Scholar 

  52. Perides G, Zhuge Y, Lin T, Stins MF, Bronson RT, Wu JK (2006) The fibrinolytic system facilitates tumor cell migration across the blood-brain barrier in experimental melanoma brain metastasis. BMC Cancer 6:56. doi:10.1186/1471-2407-6-56

    Article  PubMed  PubMed Central  Google Scholar 

  53. Kozlova N, Samoylenko A, Drobot L, Kietzmann T (2016) Urokinase is a negative modulator of Egf-dependent proliferation and motility in the two breast cancer cell lines MCF-7 and MDA-MB-231. Mol Carcinog 55:170–181. doi:10.1002/mc.22267

    Article  CAS  PubMed  Google Scholar 

  54. Beaulieu LM, Whitley BR, Wiesner TF, Rehault SM, Palmieri D, Elkahloun AG, Church FC (2007) Breast cancer and metabolic syndrome linked through the plasminogen activator inhibitor-1 cycle. BioEssays 29:1029–1038. doi:10.1002/bies.20640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. George J, Gondi CS, Dinh DH, Gujrati M, Rao JS (2007) Restoration of tissue factor pathway inhibitor-2 in a human glioblastoma cell line triggers caspase-mediated pathway and apoptosis. Clin Cancer Res 13:3507–3517. doi:10.1158/1078-0432.CCR-06-3023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dunn SE (2000) Insulin-like growth factor I stimulates angiogenesis and the production of vascular endothelial growth factor. Growth Horm IGF Res 10(Suppl A):S41–S42

    Article  PubMed  Google Scholar 

  57. Chandrasekar N, Mohanam S, Gujrati M, Olivero WC, Dinh DH, Rao JS (2003) Downregulation of uPA inhibits migration and PI3 k/Akt signaling in glioblastoma cells. Oncogene 22:392–400. doi:10.1038/sj.onc.1206164

    Article  CAS  PubMed  Google Scholar 

  58. Malinowsky K, Wolff C, Berg D, Schuster T, Walch A, Bronger H, Mannsperger H, Schmidt C, Korf U, Hofler H, Becker KF (2012) uPA and PAI-1-related signaling pathways differ between primary breast cancers and lymph node metastases. Transl Oncol 5:98–104

    Article  PubMed  PubMed Central  Google Scholar 

  59. Bajou K, Noel A, Gerard RD, Masson V, Brunner N, Holst-Hansen C, Skobe M, Fusenig NE, Carmeliet P, Collen D, Foidart JM (1998) Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 4:923–928

    Article  CAS  PubMed  Google Scholar 

  60. Gutierrez LS, Schulman A, Brito-Robinson T, Noria F, Ploplis VA, Castellino FJ (2000) Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. Cancer Res 60:5839–5847

    CAS  PubMed  Google Scholar 

  61. Sharma MR, Koltowski L, Ownbey RT, Tuszynski GP, Sharma MC (2006) Angiogenesis-associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression. Exp Mol Pathol 81:146–156. doi:10.1016/j.yexmp.2006.03.003

    Article  CAS  PubMed  Google Scholar 

  62. Hembrough TA, Kralovich KR, Li L, Gonias SL (1996) Cytokeratin 8 released by breast carcinoma cells in vitro binds plasminogen and tissue-type plasminogen activator and promotes plasminogen activation. Biochem J 317(Pt 3):763–769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Suarez-Arroyo IJ, Feliz-Mosquea YR, Perez-Laspiur J, Arju R, Giashuddin S, Maldonado-Martinez G, Cubano LA, Schneider RJ, Martinez-Montemayor MM (2016) The proteome signature of the inflammatory breast cancer plasma membrane identifies novel molecular markers of disease. Am J Cancer Res 6:1720–1740

    PubMed  PubMed Central  Google Scholar 

  64. Kim YT, Kim SK, Jeon YJ, Park SJ (2014) Seahorse-derived peptide suppresses invasive migration of HT1080 fibrosarcoma cells by competing with intracellular alpha-enolase for plasminogen binding and inhibiting uPA-mediated activation of plasminogen. BMB Rep 47:691–696

    Article  PubMed  PubMed Central  Google Scholar 

  65. Song Y, Luo Q, Long H, Hu Z, Que T, Zhang X, Li Z, Wang G, Yi L, Liu Z, Fang W, Qi S (2014) Alpha-enolase as a potential cancer prognostic marker promotes cell growth, migration, and invasion in glioma. Mol Cancer 13:65. doi:10.1186/1476-4598-13-65

    Article  PubMed  PubMed Central  Google Scholar 

  66. Rodriguez MI, Peralta-Leal A, O’Valle F, Rodriguez-Vargas JM, Gonzalez-Flores A, Majuelos-Melguizo J, Lopez L, Serrano S, de Herreros AG, Rodriguez-Manzaneque JC, Fernandez R, Del Moral RG, de Almodovar JM, Oliver FJ (2013) PARP-1 regulates metastatic melanoma through modulation of vimentin-induced malignant transformation. PLoS Genet 9:e1003531. doi:10.1371/journal.pgen.1003531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Jin H, Morohashi S, Sato F, Kudo Y, Akasaka H, Tsutsumi S, Ogasawara H, Miyamoto K, Wajima N, Kawasaki H, Hakamada K, Kijima H (2010) Vimentin expression of esophageal squamous cell carcinoma and its aggressive potential for lymph node metastasis. Biomed Res 31:105–112

    Article  CAS  PubMed  Google Scholar 

  68. Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA (2008) Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res 68:3645–3654. doi:10.1158/0008-5472.can-07-2938

    Article  CAS  PubMed  Google Scholar 

  69. Fei F, Zhang D, Yang Z, Wang S, Wang X, Wu Z, Wu Q, Zhang S (2015) The number of polyploid giant cancer cells and epithelial-mesenchymal transition-related proteins are associated with invasion and metastasis in human breast cancer. J Exp Clin Cancer Res 34:158. doi:10.1186/s13046-015-0277-8

    Article  PubMed  PubMed Central  Google Scholar 

  70. Le Bras GF, Taubenslag KJ, Andl CD (2012) The regulation of cell-cell adhesion during epithelial-mesenchymal transition, motility and tumor progression. Cell Adh Migr 6:365–373. doi:10.4161/cam.21326

    Article  PubMed  PubMed Central  Google Scholar 

  71. Pecina-Slaus N (2003) Tumor suppressor gene E-cadherin and its role in normal and malignant cells. Cancer Cell Int 3:17. doi:10.1186/1475-2867-3-17

    Article  PubMed  PubMed Central  Google Scholar 

  72. Zhou J, Tao D, Xu Q, Gao Z, Tang D (2015) Expression of E-cadherin and vimentin in oral squamous cell carcinoma. Int J Clin Exp Pathol 8:3150–3154

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Satelli A, Li S (2011) Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci 68:3033–3046. doi:10.1007/s00018-011-0735-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Xu H, Tian Y, Yuan X, Wu H, Liu Q, Pestell RG, Wu K (2015) The role of CD44 in epithelial-mesenchymal transition and cancer development. Onco Targets Ther 8:3783–3792. doi:10.2147/OTT.S95470

    PubMed  PubMed Central  Google Scholar 

  75. Louderbough JM, Brown JA, Nagle RB, Schroeder JA (2011) CD44 promotes epithelial mammary gland development and exhibits altered localization during cancer progression. Genes Cancer 2:771–781. doi:10.1177/1947601911428223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bourguignon LY, Singleton PA, Zhu H, Diedrich F (2003) Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression. J Biol Chem 278:29420–29434. doi:10.1074/jbc.M301885200

    Article  CAS  PubMed  Google Scholar 

  77. Ghatak S, Misra S, Toole BP (2002) Hyaluronan oligosaccharides inhibit anchorage-independent growth of tumor cells by suppressing the phosphoinositide 3-kinase/Akt cell survival pathway. J Biol Chem 277:38013–38020. doi:10.1074/jbc.M202404200

    Article  CAS  PubMed  Google Scholar 

  78. Deryugina EI, Quigley JP (2012) Cell surface remodeling by plasmin: a new function for an old enzyme. J Biomed Biotechnol 2012:564259. doi:10.1155/2012/564259

    Article  PubMed  PubMed Central  Google Scholar 

  79. Sousa LP, Silva BM, Brasil BS, Nogueira SV, Ferreira PC, Kroon EG, Kato K, Bonjardim CA (2005) Plasminogen/plasmin regulates alpha-enolase expression through the MEK/ERK pathway. Biochem Biophys Res Commun 337:1065–1071. doi:10.1016/j.bbrc.2005.09.154

    Article  CAS  PubMed  Google Scholar 

  80. Bazzi ZA, Lanoue D, El-Youssef M, Romagnuolo R, Tubman J, Cavallo-Medved D, Porter LA, Boffa MB (2016) Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) attenuates breast cancer cell metastatic behaviors through inhibition of plasminogen activation and extracellular proteolysis. BMC Cancer 16:328. doi:10.1186/s12885-016-2359-1

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT), Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM), grant number IN 223014, Viedma-Rodríguez R and Flores-López LA were postdoctoral fellows of DGAPA, UNAM.

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  1. Unidad de Morfofisiología, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, 54090, Tlalnepantla, Estado de México, Mexico

    Rubí Viedma-Rodríguez, María Guadalupe Martínez-Hernández, Luis Antonio Flores-López & Luis Arturo Baiza-Gutman

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  1. Rubí Viedma-Rodríguez
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Correspondence to Luis Arturo Baiza-Gutman.

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Viedma-Rodríguez, R., Martínez-Hernández, M.G., Flores-López, L.A. et al. Epsilon-aminocaproic acid prevents high glucose and insulin induced-invasiveness in MDA-MB-231 breast cancer cells, modulating the plasminogen activator system. Mol Cell Biochem 437, 65–80 (2018). https://doi.org/10.1007/s11010-017-3096-8

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