Molecular and Cellular Biochemistry

, Volume 287, Issue 1–2, pp 109–116 | Cite as

Quercetin downregulates matrix metalloproteinases 2 and 9 proteins expression in prostate cancer cells (PC-3)

  • M. R. Vijayababu
  • A. Arunkumar
  • P. Kanagaraj
  • P. Venkataraman
  • G. Krishnamoorthy
  • J. ArunakaranEmail author


Background: Cancer metastasis, involving multiple processes and various cytophysiological changes, is a primary cause of cancer death and may complicate the clinical management, even lead to death. Quercetin is a flavonoid and widely used as an antioxidant and recent studies have revealed its pleiotropic anticancer and antiproliferative capabilities. Gelatinases A and B (matrixmetalloproteinases 2 and 9) are enzymes known to involve in tumor invasion and metastases. In this study, we observed the precise involvement of quercetin role on these proteinases expression and activity. Design and methods: PC-3 cells were treated with quercetin at various concentrations (50 and 100 μM), for 24 h period and then subjected to western blot analysis to investigate the impact of quercetin on matrix metalloproteinase-2 (MMP-2) and 9 (MMP-9) expressions. Conditioned medium and cell lysate of quercetin-treated PC-3 cells were subjected to western blot analysis for proteins expression of MMP-2 and MMP-9. Gelatin zymography was also performed in quercetin treated PC-3 cells. Results: The results showed that quercetin treatment decreased the expressions of MMP-2 and MMP-9 in dose-dependent manner. The level of pro-MMP-9 was found to be high in the 100 μM quercetin-treated cell lysate of PC-3 cells, suggesting inhibitory role of quercetin on pro-MMP-9 activation. Gelatin zymography study also showed the decreased activities of MMP-2 and MMP-9 in quercetin treated cells. Conclusion: Hence, we speculated that inhibition of metastasis-specific MMPs in cancer cells may be one of the targets for anticancer function of quercetin, and thus provides the molecular basis for the development of quercetin as a novel chemopreventive agent for metastatic prostate cancer.

Key words

prostate cancer quercetin matrixmetalloproteinases metastases PC-3 cells 


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  1. 1.
    Liotta LA, Stetler-Stevenson WG: Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res 51: 5054–5059, 1991Google Scholar
  2. 2.
    Stetler-Stevenson WG, Liotta LA, Kleiner DE Jr: Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J 7: 1434–1441, 1993PubMedGoogle Scholar
  3. 3.
    Hojilla CV, Mohammed FF, Khokha R: Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development. Brit J Cancer 89: 1817–1821, 2003PubMedCrossRefGoogle Scholar
  4. 4.
    Stetler-Stevenson WG: Matrix metallo proteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest 103: 1237–1241, 1999PubMedCrossRefGoogle Scholar
  5. 5.
    Zhang L, Shi J, Feng J, Klocker H, Lee C, Zhang J: Type IV collagenase (matrix metalloproteinase-2 and -9) in prostate cancer. Prostate Cancer Prostatic Dis 7: 327–332, 2004PubMedCrossRefGoogle Scholar
  6. 6.
    Taraphdar AK, Roy M, Bhattacharya RK: Natural products as inducers of apoptosis: Implication for cancer therapy and prevention. Curr Sci 80: 1387–1396, 2001Google Scholar
  7. 7.
    Csokay B, Prajda N, Weber G, Olah E: Molecular mechanisms in the antiproliferative action of quercetin. Life Sci 60: 2157–2163, 1997PubMedCrossRefGoogle Scholar
  8. 8.
    Ferriola PC, Cody V, Middleton E Jr.: Protein-kinase C inhibition by plant flavonoids. Kinetic mechanisms and structure-activity relationship. Biochem Pharmacol 38: 1617–1624, 1989Google Scholar
  9. 9.
    Casagrande F, Darbon JM: Effects of structurally related flavonoids on cell cycle progression of human melanoma cells: regulation of cyclin-dependent kinases CDK2 and CDK1. Biochem Pharmacol 61: 1205–1215, 2001PubMedCrossRefGoogle Scholar
  10. 10.
    Nguyen TT, Tran E, Nguyen TH, Do PT, Huynh TH, Huynh H: The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. Carcinogenesis 25: 647–659, 2004PubMedCrossRefGoogle Scholar
  11. 11.
    Vijayababu MR, Kanagaraj P, Arunkumar A, Aruldhas MM, Arunakaran J: Quercetin-induced growth inhibition and cell death in prostatic carcinoma cells (PC-3) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression. J Cancer Res Clin Oncol, 2005 131:765–771.PubMedCrossRefGoogle Scholar
  12. 12.
    Kaighn ME, Narayan KS, Ohnuki Y, Lechner JF, Jones LW: Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Investigative Urol 17: 16–23, 1979Google Scholar
  13. 13.
    Aalinkeel R, Nair MP, Sufrin G, Mahajan SD, Chadha KC, Chawda RP, Schwartz SA: Gene expression of angiogenic factors correlates with metastatic potential of prostate cancer cells. Cancer Res 64: 5311–5321, 2004PubMedCrossRefGoogle Scholar
  14. 14.
    Vayalil PK, Mittal A, Katiyar SK: 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, 2004PubMedCrossRefGoogle Scholar
  15. 15.
    Martin JL, Pattison SL: Insulin-like growth factor binding protein-3 is regulated by dihydrotestosterone and stimulates deoxyribonucleic acid synthesis and cell proliferation in LNCaP prostate carcinoma cell. Endocrinology 141: 2401–2404, 2000PubMedCrossRefGoogle Scholar
  16. 16.
    Lowry OH, Risebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin-phenol reagent. J Biol Chem 193: 265–270, 1951PubMedGoogle Scholar
  17. 17.
    Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336, 1991PubMedCrossRefGoogle Scholar
  18. 18.
    Liotta LA: Cancer cell invasion and metastasis. Sci Am 266: 54–59, 1992PubMedCrossRefGoogle Scholar
  19. 19.
    Stetler-Stevenson WG: The role of matrix metalloproteinases in tumor invasion, metastasis, and angiogenesis. Surg Oncol Clin N Am 10: 383–392, 2001PubMedGoogle Scholar
  20. 20.
    Sauer CG, Kappeler A, Spath M, Kaden JJ, Michel MS, Mayer D, Bleyl U, Grobholz R: Expression and activity of matrix metalloproteinases-2 and -9 in serum, core needle biopsies and tissue specimens of prostate cancer patients. Virchows Arch 444: 518–526, 2004PubMedCrossRefGoogle Scholar
  21. 21.
    Lamson DW, Brignall MS: Antioxidants and cancer III: Quercetin. Alternative Med Rev 5: 196–208, 2000Google Scholar
  22. 22.
    Graziani Y, Erikson E, Erikson RL: The effect of the phosphorylation activity of the ras sarcoma virus transforming gene product in vitro and in vivo. Eur J Biochem 135: 583–589, 1983PubMedCrossRefGoogle Scholar
  23. 23.
    Zhang XM, Huang SP, Xu Q: Quercetin inhibits the invasion of murine melanoma B16-BL6 cells by decreasing pro-MMP-9 via the PKC pathway. Cancer Chemother Pharmacol 53: 82–88, 2004PubMedCrossRefGoogle Scholar
  24. 24.
    McDonnel SE, Kerr LD, Matrisian LM: Epidermal growth factor stimulation of stromelysin mRNA in rat fibroblasts requires induction of proto-oncogene c-fos and c-jun and activation of protein kinase C. Mol Cell Biol 10: 4284–4293, 1990Google Scholar
  25. 25.
    Davis BD, Brown PD, East N, Crimmin MJ, Balkwill FR: A synthetic matrix metalloproteinase inhibitor decrease tumor burden and prolongs survival of mice bearing human ovarian carcinoma xenografts. Cancer Res 53: 2087–2091, 1993Google Scholar
  26. 26.
    Naylor MS, Stamp GW, Davies BD, Balkwill FR: Expression and activity of MMPs and their regulators in ovarian cancer. Intl J Cancer 58: 50–56, 1994Google Scholar
  27. 27.
    Hamdy FC, Fadlon EJ, Cottam D, Lowry J, Thurrel W, Silocks PB, Anderson JB, Williams JL, Rees RC: Matrix metalloproteinase 9 expression in primary human prostatic adenocarcinoma and benign prostatic hyperplasia. Br J Cancer 69: 177–182, 1994PubMedGoogle Scholar
  28. 28.
    Liabakk NB, Talbot I, Smith RA, Wilkinson K, Balkwill F: Matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res 56: 190–196, 1996PubMedGoogle Scholar
  29. 29.
    Watson SA, Morris TM, Robinson G, Crimmin MJ, Brown PD, Hardcastle JD: Inhibition of organ invasion by the metalloproteinase inhibitor Batimastat (BB-94) in two human colon carcinoma metastasis models. Cancer Res 55: 3629–3633, 1995PubMedGoogle Scholar
  30. 30.
    Cha IJ, Bae SK, Lee HY, Lee OH, Sato H, Seiki M, Park BC, Kim KW: Anti-invasive activity of ursolic acid correlates with the reduced expression of matrix metalloproteinase-9 (MMP-9) in HT-1089 human fibrosacoma cells. Cancer Res 56: 2281–2284, 1996PubMedGoogle Scholar
  31. 31.
    Matrisian LM: Metalloproteinases and their inhibitors in matrix remolding. Trends Genet 6: 121–125, 1990PubMedCrossRefGoogle Scholar
  32. 32.
    Kerr LD, Holt JT, Matrisian LM: Growth factors regulate transin gene expression by c-fos and c-fos independent pathways. Science 242: 1424–1427, 1988PubMedGoogle Scholar
  33. 33.
    McDonnel SE, Fingleton B: Role of matrix metalloproteinase in invasion and metastasis: biology, diagnosis and inhibitors. Cytotechnology 12: 367–384, 1993CrossRefGoogle Scholar
  34. 34.
    Bredin CG, Liu Z, Klominek J: Growth factor-enhanced expression and activity of matrix metalloproteases in human non-small cell lung cancer cell lines. Anticancer Res 23:4877–4884, 2003PubMedGoogle Scholar
  35. 35.
    Zhang D, Samani AA, Brodt P: The role of the IGF-I receptor in the regulation of matrix metalloproteinases, tumor invasion and metastasis. Horm Metab Res 35: 802–808, 2003PubMedCrossRefGoogle Scholar
  36. 36.
    Scholar EM, Toews ML: Inhibition of invasion of murine mammary carcinoma cells by the tyrosine kinase inhibitor genistein. Cancer Lett 87: 159–162, 1994PubMedCrossRefGoogle Scholar
  37. 37.
    Vijayababu MR, Kanagaraj P, Arunkumar A, Srinivasan N, Aruldhas MM, Arunakaran J: Effects of quercetin on IGF system components in PC-3 cells. XXII symposium of the Society for Reproductive Biology and Comparative Endocrinology (SRBCE), University of Madras, Chennai, India, 2004Google Scholar
  38. 38.
    Song L, Xu M, Lopes-Virella MF, Huang Y: Quercetin inhibits matrix metalloproteinase-1 expression in human vascular endothelial cells through extracellular signal-regulated kinase. Arch Biochem Biophys 391: 72–78, 2001PubMedCrossRefGoogle Scholar
  39. 39.
    Ferry DR, Smith A, Malkhandi J, Fyfe DW, deTakats PG, Anderson D, Baker J, Kerr DJ: Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 2: 659–668, 1996PubMedGoogle Scholar
  40. 40.
    Huang YT, Hwang JJ, Lee PP, Ke FC, Huang JH, Huang CJ, Kandaswami C, Middleton E Jr, Lee MT: Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis-associated properties in A431 cells over expressing epidermal growth factor receptor. Brit J Pharmacol 128: 999–1010, 1999CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • M. R. Vijayababu
    • 1
  • A. Arunkumar
    • 1
  • P. Kanagaraj
    • 1
  • P. Venkataraman
    • 1
  • G. Krishnamoorthy
    • 1
  • J. Arunakaran
    • 1
    Email author
  1. 1.Department of Endocrinology, Dr. ALM Postgraduate Institute of Basic Medical SciencesUniversity of MadrasChennaiIndia

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