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Grape seed extract suppresses MDA-MB231 breast cancer cell migration and invasion

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Abstract

Background and aim

Breast cancer remains a leading cause of mortality among women. In metastasis, cascade migration of cancer cells and invasion of extracellular matrix (ECM) represent critical steps. Urokinase-type plasminogen activator (uPA), as well as metalloproteinases MMP-2 and MMP-9, strongly contribute to ECM remodelling, thus becoming associated with tumour migration and invasion. In addition, the high expression of cytoskeletal (CSK) proteins, as fascin, has been correlated with clinically aggressive metastatic tumours, and CSK proteins are thought to affect the migration of cancer cells. Consumption of fruits and vegetables, characterized by high procyanidin content, has been associated to a reduced mortality for breast cancer. Therefore, we investigated the biological effect of grape seed extract (GSE) on the highly metastatic MDA-MB231 breast cancer cell line, focusing on studying GSE ability in inhibiting two main metastatic processes, i.e., cell migration and invasion.

Methods

After MDA-MB231 breast cancer cells stimulated with GSE migration and invasion were evaluated by means of trans-well assays and uPA as well as MMPs activity was detected by gelatin zymography. Fascin, β-catenin and nuclear factor-κB (NF-κB) expression were determined using western blot technique. β-Catenin localization was observed by confocal microscopy.

Results

We observed that high concentrations of GSE inhibited cell proliferation and apoptosis. Conversely, low GSE concentration decreased cell migration and invasion, likely by hampering β-catenin expression and localization, fascin and NF-κB expression, as well as by decreasing the activity of uPA, MMP-2 and MMP-9.

Conclusions

These results make GSE a powerful candidate for developing preventive agents against cancer metastasis.

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References

  1. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  CAS  Google Scholar 

  2. Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12:895–904

    Article  CAS  Google Scholar 

  3. Bogenrieder T, Herlyn M (2003) Axis of evil: molecular mechanisms of cancer metastasis. Oncogene 22:6524–6536

    Article  CAS  Google Scholar 

  4. Jezierska A, Motyl T (2009) Matrix metalloproteinase-2 involvement in breast cancer progression: a mini-review. Med Sci Monit 15:RA32–RA40

    CAS  Google Scholar 

  5. Alexander CM, Werb Z (1991) Extracellular matrix degradation. Plenum Press, New York, pp 255–302

    Google Scholar 

  6. Mignatti P, Rifkin DB (1993) Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 73:161–195

    CAS  Google Scholar 

  7. Danø K, Andreasen PA, Grøndahl-Hansen J et al (1985) Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 44:139–266

    Article  Google Scholar 

  8. Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52–67

    Article  CAS  Google Scholar 

  9. Lin KL, Tsai PC, Hsieh CY et al (2011) Antimetastatic effect and mechanism of ovatodiolide in MDA-MB-231 human breast cancer cells. Chem Biol Interact 194:148–158

    Article  CAS  Google Scholar 

  10. Jiang P, Enomoto A, Takahashi M (2009) Cell biology of the movement of breast cancer cells: intracellular signalling and the actin cytoskeleton. Cancer Lett 284:122–130

    Article  CAS  Google Scholar 

  11. Vignjevic D, Kojima S, Aratyn Y et al (2006) Role of fascin in filopodial protrusion. J Cell Biol 174:863–875

    Article  CAS  Google Scholar 

  12. Edwards RA, Bryan J (1995) Fascins, a family of actin bundling proteins. Cell Motil Cytoskelet 32:1–9

    Article  CAS  Google Scholar 

  13. Vignjevic D, Schoumacher M, Gavert N et al (2007) Fascin, a novel target of beta-catenin-TCF signaling, is expressed at the invasive front of human colon cancer. Cancer Res 67:6844–6853

    Article  CAS  Google Scholar 

  14. Brabletz T, Jung A, Hermann K et al (1998) Nuclear overexpression of the oncoprotein β-catenin in colorectal cancer is localized predominantly at the invasion front. Pathol Res Pract 194:701–704

    Article  CAS  Google Scholar 

  15. Gavert N, Conacci-Sorrell M, Gast D et al (2005) L1, a novel target of h-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers. J Cell Biol 168:633–642

    Article  CAS  Google Scholar 

  16. Al-Alwan M, Olabi S, Ghebeh H et al (2011) Fascin is a key regulator of breast cancer invasion that acts via the modification of metastasis-associated molecules. PLoS One 6:e27339

    Article  CAS  Google Scholar 

  17. Westermarck J, Kähäri VM (1999) Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13:781–792

    CAS  Google Scholar 

  18. Lokeshwar BL (1999) MMP inhibition in prostate cancer. Ann NY Acad Sci 878:271–289

    Article  CAS  Google Scholar 

  19. Brawley OW, Barnes S, Parnes H (2001) The future of prostate cancer prevention. Ann NY Acad Sci 952:145–152

    Article  CAS  Google Scholar 

  20. Palmer S (1985) Diet, nutrition, and cancer. Prog Food Nutr Sci 9:283–341

    CAS  Google Scholar 

  21. Dinicola S, Cucina A, Pasqualato A et al (2010) Apoptosis-inducing factor and caspase-dependent apoptotic pathways triggered by different grape seed extracts on human colon cancer cell line Caco-2. Br J Nutr 104:824–832

    Article  CAS  Google Scholar 

  22. Dinicola S, Cucina A, Pasqualato A et al (2012) Antiproliferative and apoptotic effects triggered by grape seed extract (GSE) versus epigallocatechin and procyanidins on colon cancer cell lines. Int J Mol Sci 13:651–664

    Article  CAS  Google Scholar 

  23. Dinicola S, Mariggiò MA, Morabito C et al (2013) Grape seed extract triggers apoptosis in Caco-2 human colon cancer cells through reactive oxygen species and calcium increase: extracellular signal-regulated kinase involvement. Br J Nutr. doi:10.1017/S0007114512006095

    Google Scholar 

  24. Sharma G, Tyagi AK, Singh RP et al (2004) Synergistic anti-cancer effects of grape seed extract and conventional cytotoxic agent doxorubicin against human breast carcinoma cells. Breast Cancer Res Treat 85:1–12

    Article  CAS  Google Scholar 

  25. Cavaliere C, Foglia P, Gubbiotti R et al (2008) Rapid-resolution liquid chromatography/mass spectrometry for determination and quantitation of polyphenols in grape berries. Rapid Commun Mass Spectrom 22:3089–3099

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Belin D, Godeau F, Vassalli JD (1984) Tumor promoter PMA stimulates the synthesis and secretion of mouse pro-urokinase in MSV-transformed 3T3 cells: this is mediated by an increase in urokinase mRNA content. EMBO J 3:1901–1906

    CAS  Google Scholar 

  28. Nandakumar V, Singh T, Katiyar SK (2008) Multi-targeted prevention and therapy of cancer by proanthocyanidins. Cancer Lett 269:378–387

    Article  CAS  Google Scholar 

  29. Joshi SS, Kuszynski CA, Bagchi D (2001) The cellular and molecular basis of health benefits of grape seed proanthocyanidin extract. Curr Pharm Biotechnol 2:187–200

    Article  CAS  Google Scholar 

  30. Saeki K, Hayakawa S, Isemura M et al (2000) Importance of a pyrogallol-type structure in catechin compounds for apoptosis-inducing activity. Phytochemistry 53:391–394

    Article  CAS  Google Scholar 

  31. Wu PP, Kuo SC, Huang WW et al (2009) (-)-Epigallocatechin gallate induced apoptosis in human adrenal cancer NCI-H295 cells through caspase-dependent and caspase-independent pathway. Anticancer Res 29:1435–1442

    CAS  Google Scholar 

  32. Ling H, Zhang Y, Ng KY et al (2011) Pachymic acid impairs breast cancer cell invasion by suppressing nuclear factor-κB-dependent matrix metalloproteinase-9 expression. Breast Cancer Res Treat 126:609–620

    Article  CAS  Google Scholar 

  33. Ko HS, Lee HJ, Kim SH et al (2012) Piceatannol suppresses breast cancer cell invasion through the Inhibition of MMP-9: involvement of PI3K/AKT and NF-κB Pathways. J Agric Food Chem 60:4083–4089

    Article  CAS  Google Scholar 

  34. Kim S, Han J, Lee SK et al (2011) Berberine suppresses the TPA-induced MMP-1 and MMP-9 expressions through the inhibition of PKC-α in breast cancer cells. J Surg Res 176:21–29

    Article  Google Scholar 

  35. Vayalil PK, Mittal A, Katiyar SK (2004) Proanthocyanidins from grape seeds inhibit expression of matrix metalloproteinases in human prostate carcinoma cells, which is associated with the inhibition of activation of MAPK and NF kappa B. Carcinogenesis 25:987–995

    Article  CAS  Google Scholar 

  36. Vayalil PK, Katiyar SK (2004) Treatment of epigallocatechin-3-gallate inhibits matrix metalloproteinases-2 and -9 via inhibition of activation of mitogen-activated protein kinases, c-jun and NF-kappaB in human prostate carcinoma DU-145 cells. Prostate 59:33–42

    Article  CAS  Google Scholar 

  37. Duffy MJ, Maguire TM, Hill A et al (2000) Metalloproteinases: role in breast carcinogenesis, invasion and metastasis. Breast Cancer Res 2:252–257

    Article  CAS  Google Scholar 

  38. Zucker S, Hymowitz M, Conner C et al (1999) Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications. Ann NY Acad Sci 878:212–227

    Article  CAS  Google Scholar 

  39. Yang SF, Chen MK, Hsieh YS et al (2010) Antimetastatic effects of Terminalia catappa L. on oral cancer via a down-regulation of metastasis-associated proteases. Food Chem Toxicol 48:1052–1058

    Article  CAS  Google Scholar 

  40. Aguirre Ghiso JA, Alonso DF, Farías EF et al (1999) Deregulation of the signaling pathways controlling urokinase production. Its relationship with the invasive phenotype. Eur J Biochem 263:295–304

    Article  CAS  Google Scholar 

  41. Sliva D (2004) Signaling pathways responsible for cancer cell invasion as targets for cancer therapy. Curr Cancer Drug Targets 4:327–336

    Article  CAS  Google Scholar 

  42. Takada Y, Singh S, Aggarwal BB (2004) Identification of a p65 peptide that selectively inhibits NF-kappa B activation induced by various inflammatory stimuli and its role in down-regulation of NF-kappaB-mediated gene expression and up-regulation of apoptosis. J Biol Chem 279:15096–15104

    Article  CAS  Google Scholar 

  43. Aggarwal BB (2004) Nuclear factor-kappaB: the enemy within. Cancer Cell 6:203–208

    Article  CAS  Google Scholar 

  44. Snyder M, Huang XY, Zhang JJ (2011) Signal transducers and activators of transcription 3 (STAT3) directly regulates cytokine-induced fascin expression and is required for breast cancer cell migration. J Biol Chem 286:38886–38893

    Article  CAS  Google Scholar 

  45. Adams JC (2004) Roles of fascin in cell adhesion and motility. Curr Opin Cell Biol 16:590–596

    Article  CAS  Google Scholar 

  46. Machesky LM, Li A (2010) Fascin: invasive filopodia promoting metastasis. Commun Integr Biol 3:263–270

    Article  Google Scholar 

  47. Jamieson C, Sharma M, Henderson BR (2012) Wnt signaling from membrane to nucleus: β-catenin caught in a loop. Int J Biochem Cell Biol 44:847–850

    Article  CAS  Google Scholar 

  48. Valenta T, Hausmann G, Basler K (2012) The many faces and functions of β-catenin. EMBO J 31:2714–2736

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Dr. D. Antonacci for providing the grape seed extract, and to professors G. Pasqua and A. Laganà for chemical characterization of the extract.

Conflict of interest

On behalf of all authors, the corresponding author (Mariano Bizzari) states that there is no conflict of interests.

Author information

Authors and Affiliations

  1. Department of Clinical and Molecular Medicine, La Sapienza University, Piazza Sassari 3, 00161, Rome, Italy

    Simona Dinicola, Sara Proietti & Alessandro Palombo

  2. Department of Surgery “P. Valdoni”, La Sapienza University, Via A. Scarpa 14, 00161, Rome, Italy

    Simona Dinicola, Alessia Pasqualato, Alessandra Cucina, Pierpaolo Coluccia, Sara Proietti & Alessandro Palombo

  3. Department of Neuroscience and Imaging-Centro Studi sull’Invecchiamento (CeSI), G. d’Annunzio University, Via dei Vestini 31, 66013, Chieti, Italy

    Alessia Pasqualato

  4. Italian Space Agency (ASI), Viale Liegi, 26, 00198, Rome, Italy

    Francesca Ferranti

  5. Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Section of Histology and Embryology, School of Pharmacy and Medicine, La Sapienza University, Via A. Scarpa 16, 00161, Rome, Italy

    Francesca Ferranti, Rita Canipari & Angela Catizone

  6. Department of Experimental Medicine, La Sapienza University, Viale Regina Elena, 324, 00161, Rome, Italy

    Fabrizio D’Anselmi & Mariano Bizzarri

  7. Department of Experimental Medicine, Histology and Embryology Laboratory, School of Medicine, Second University of Naples, Via L. Armanni 5, 80138, Naples, Italy

    Giulia Ricci

  8. Via A. Scarpa 14, 00161, Rome, Italy

    Mariano Bizzarri

Authors
  1. Simona Dinicola
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  2. Alessia Pasqualato
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  3. Alessandra Cucina
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  4. Pierpaolo Coluccia
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  5. Francesca Ferranti
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  6. Rita Canipari
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  7. Angela Catizone
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  8. Sara Proietti
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  9. Fabrizio D’Anselmi
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  10. Giulia Ricci
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  11. Alessandro Palombo
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  12. Mariano Bizzarri
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Corresponding author

Correspondence to Mariano Bizzarri.

Additional information

Dinicola Simona and Pasqualato Alessia contributed equally to this work.

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Dinicola, S., Pasqualato, A., Cucina, A. et al. Grape seed extract suppresses MDA-MB231 breast cancer cell migration and invasion. Eur J Nutr 53, 421–431 (2014). https://doi.org/10.1007/s00394-013-0542-6

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  • DOI: https://doi.org/10.1007/s00394-013-0542-6

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