Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Inhibition of cyclooxygenase-2-mediated matriptase activation contributes to the suppression of prostate cancer cell motility and metastasis

Oncogene volume 36, pages 4597–4609 (2017)Cite this article

Subjects

Abstract

Chronic inflammation plays an important role in cancer development and progression. Cyclooxygenases-2 (COX-2) is a key enzyme in generating prostaglandins causing inflammation, is often found to be overexpressed in prostate cancer (PCa) and is correlated with PCa cell invasion and metastasis. We aim to investigate the molecular mechanism of how COX-2 promotes PCa cell invasion and metastasis and to evaluate the effect of COX-2 inhibitors in a selected model of PCa progression. Our results showed that the expression of COX-2 and Interleukin 1β (IL-1β) was upregulated in highly invasive PCa cells and was correlated with the activated levels of membrane-anchored serine protease matriptase. The expression levels of COX-2 were increased and were correlated with matriptase levels in PCa specimens. Moreover, results showed that COX-2 overexpression or a COX-2 product Prostaglandin E2 (PGE2) caused an increase in matriptase activation and PCa cell invasion, whereas COX-2 silencing antagonized matriptase activation and cell invasion. In addition, the inhibition of COX-2-mediated matriptase activation by Celebrex and sulindac sulfide suppressed the androgen-independent and COX2-overexpressing PCa PC-3 cell invasion, tumor growth and lung metastasis in an orthotopic xenograft model. Our results indicate that COX-2/matriptase signaling contributes to the invasion, tumor growth and metastasis of COX-2-overexpressing and androgen-independent PCa cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Coussens LM, Werb Z . Inflammation and cancer. Nature 2002; 420: 860–867.

    Article  CAS  Google Scholar 

  2. Cerutti PA, Trump BF . Inflammation and oxidative stress in carcinogenesis. Cancer Cells 1991; 3: 1–7.

    CAS  PubMed  Google Scholar 

  3. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H, Drake CG et al. Inflammation in prostate carcinogenesis. Nat rev Cancer 2007; 7: 256–269.

    Article  CAS  Google Scholar 

  4. Nelson WG, De Marzo AM, DeWeese TL, Isaacs WB . The role of inflammation in the pathogenesis of prostate cancer. J Urol 2004; 172: S6–S11; discussion S11–S12.

    Article  CAS  Google Scholar 

  5. Rao P, Knaus EE . Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J Pharm Pharm Sci 2008; 11: 81s–110s.

    Article  Google Scholar 

  6. Kirschenbaum A, Klausner AP, Lee R, Unger P, Yao S, Liu XH et al. Expression of cyclooxygenase-1 and cyclooxygenase-2 in the human prostate. Urology 2000; 56: 671–676.

    Article  CAS  Google Scholar 

  7. Amano H, Hayashi I, Endo H, Kitasato H, Yamashina S, Maruyama T et al. Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth. J exp med 2003; 197: 221–232.

    Article  CAS  Google Scholar 

  8. Wang D, Dubois RN . Eicosanoids and cancer. Nat rev Cancer 2010; 10: 181–193.

    Article  CAS  Google Scholar 

  9. Sugimoto Y, Narumiya S . Prostaglandin E receptors. J Biol Chem 2007; 282: 11613–11617.

    Article  CAS  Google Scholar 

  10. Gupta RA, Dubois RN . Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat rev Cancer 2001; 1: 11–21.

    Article  CAS  Google Scholar 

  11. Rundhaug JE, Simper MS, Surh I, Fischer SM . The role of the EP receptors for prostaglandin E2 in skin and skin cancer. Cancer Metastasis Rev 2011; 30: 465–480.

    Article  CAS  Google Scholar 

  12. Ansari KM, Rundhaug JE, Fischer SM . Multiple signaling pathways are responsible for prostaglandin E2-induced murine keratinocyte proliferation. Mol cancer res 2008; 6: 1003–1016.

    Article  CAS  Google Scholar 

  13. O'Neill GP, Ford-Hutchinson AW . Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett 1993; 330: 156–160.

    Article  CAS  Google Scholar 

  14. Gupta S, Srivastava M, Ahmad N, Bostwick DG, Mukhtar H . Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma. Prostate 2000; 42: 73–78.

    Article  CAS  Google Scholar 

  15. Lee LM, Pan CC, Cheng CJ, Chi CW, Liu TY . Expression of cyclooxygenase-2 in prostate adenocarcinoma and benign prostatic hyperplasia. Anticancer res 2001; 21: 1291–1294.

    CAS  PubMed  Google Scholar 

  16. Shi YE, Torri J, Yieh L, Wellstein A, Lippman ME, Dickson RB . Identification and characterization of a novel matrix-degrading protease from hormone-dependent human breast cancer cells. Cancer Res 1993; 53: 1409–1415.

    CAS  PubMed  Google Scholar 

  17. Lee MS, Kiyomiya K, Benaud C, Dickson RB, Lin CY . Simultaneous activation and hepatocyte growth factor activator inhibitor 1-mediated inhibition of matriptase induced at activation foci in human mammary epithelial cells. Am J Physiol Cell Physiol 2005; 288: C932–C941.

    Article  CAS  Google Scholar 

  18. Benaud C, Oberst M, Hobson JP, Spiegel S, Dickson RB, Lin CY . Sphingosine 1-phosphate, present in serum-derived lipoproteins, activates matriptase. J Biol Chem 2002; 277: 10539–10546.

    Article  CAS  Google Scholar 

  19. Kiyomiya K, Lee MS, Tseng IC, Zuo H, Barndt RJ, Johnson MD et al. Matriptase activation and shedding with HAI-1 is induced by steroid sex hormones in human prostate cancer cells, but not in breast cancer cells. Am J Physiol Cell Physiol 2006; 291: C40–C49.

    Article  CAS  Google Scholar 

  20. Ko CJ, Huang CC, Lin HY, Juan CP, Lan SW, Shyu HY et al. Androgen-induced TMPRSS2 activates matriptase and promotes extracellular matrix degradation, prostate cancer cell invasion, tumor growth, and metastasis. Cancer Res 2015; 75: 2949–2960.

    Article  CAS  Google Scholar 

  21. Saleem M, Adhami VM, Zhong W, Longley BJ, Lin CY, Dickson RB et al. A novel biomarker for staging human prostate adenocarcinoma: overexpression of matriptase with concomitant loss of its inhibitor, hepatocyte growth factor activator inhibitor-1. Cancer Epidemiol Biomarkers Prev 2006; 15: 217–227.

    Article  CAS  Google Scholar 

  22. Wu SR, Cheng TS, Chen WC, Shyu HY, Ko CJ, Huang HP et al. Matriptase is involved in ErbB-2-induced prostate cancer cell invasion. Am J Pathol 2010; 177: 3145–3158.

    Article  CAS  Google Scholar 

  23. Tsai CH, Teng CH, Tu YT, Cheng TS, Wu SR, Ko CJ et al. HAI-2 suppresses the invasive growth and metastasis of prostate cancer through regulation of matriptase. Oncogene 2014; 33: 4643–4652.

    Article  CAS  Google Scholar 

  24. Galkin AV, Mullen L, Fox WD, Brown J, Duncan D, Moreno O et al. CVS-3983, a selective matriptase inhibitor, suppresses the growth of androgen independent prostate tumor xenografts. Prostate 2004; 61: 228–235.

    Article  CAS  Google Scholar 

  25. Bieniek J, Childress C, Swatski MD, Yang W . COX-2 inhibitors arrest prostate cancer cell cycle progression by down-regulation of kinetochore/centromere proteins. Prostate 2014; 74: 999–1011.

    Article  CAS  Google Scholar 

  26. Kim SH, Park WS, Park BR, Joo J, Joung JY, Seo HK et al. PSCA, Cox-2, and Ki-67 are independent, predictive markers of biochemical recurrence in clinically localized prostate cancer: a retrospective study. Asian J Androl 2016, epub ahead of print 27 May 2016; doi:10.4103/1008-682X.180798.

    Article  Google Scholar 

  27. Kattan J, Bachour M, Farhat F, El Rassy E, Assi T, Ghosn M . Phase II trial of weekly Docetaxel, Zoledronic acid, and Celecoxib for castration-resistant prostate cancer. Invest New Drugs 2016; 34: 474–480.

    Article  CAS  Google Scholar 

  28. James ND, Sydes MR, Mason MD, Clarke NW, Anderson J, Dearnaley DP et al. Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial. Lancet Oncol 2012; 13: 549–558.

    Article  CAS  Google Scholar 

  29. James ND . Celecoxib with or without zoledronic acid for hormone-naïve prostate cancer: survival results from STAMPEDE (NCT00268476). Clin Adv Hematol Oncol 2016; 14 (4 Suppl 5): 11–13.

    Google Scholar 

  30. Cheng TS, Chen WC, Lin YY, Tsai CH, Liao CI, Shyu HY et al. Curcumin-targeting pericellular serine protease matriptase role in suppression of prostate cancer cell invasion, tumor growth, and metastasis. Cancer Prev Res (Phila) 2013; 6: 495–505.

    Article  CAS  Google Scholar 

  31. Lin CY, Anders J, Johnson M, Dickson RB . Purification and characterization of a complex containing matriptase and a Kunitz-type serine protease inhibitor from human milk. J Biol Chem 1999; 274: 18237–18242.

    Article  CAS  Google Scholar 

  32. Benaud C, Dickson RB, Lin CY . Regulation of the activity of matriptase on epithelial cell surfaces by a blood-derived factor. Eur J Biochem 2001; 268: 1439–1447.

    Article  CAS  Google Scholar 

  33. Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, Paraskeva C et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 2009; 30: 377–386.

    Article  CAS  Google Scholar 

  34. Wang X, Klein RD . Prostaglandin E2 induces vascular endothelial growth factor secretion in prostate cancer cells through EP2 receptor-mediated cAMP pathway. Mol Carcinog 2007; 46: 912–923.

    Article  CAS  Google Scholar 

  35. Li Z, Zhang Y, Kim WJ, Daaka Y . PGE2 promotes renal carcinoma cell invasion through activated RalA. Oncogene 2013; 32: 1408–1415.

    Article  CAS  Google Scholar 

  36. Ruan D, So SP . Prostaglandin E2 produced by inducible COX-2 and mPGES-1 promoting cancer cell proliferation in vitro and in vivo. Life sci 2014; 116: 43–50.

    Article  CAS  Google Scholar 

  37. Wang W, Bergh A, Damber JE . Cyclooxygenase-2 expression correlates with local chronic inflammation and tumor neovascularization in human prostate cancer. Clin Cancer Res 2005; 11: 3250–3256.

    Article  CAS  Google Scholar 

  38. Di Lorenzo G, De Placido S, Autorino R, De Laurentiis M, Mignogna C, D'Armiento M et al. Expression of biomarkers modulating prostate cancer progression: implications in the treatment of the disease. Prostate Cancer Prostatic Dis 2005; 8: 54–59.

    Article  CAS  Google Scholar 

  39. Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 2001; 276: 18563–18569.

    Article  CAS  Google Scholar 

  40. Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996; 87: 803–809.

    Article  CAS  Google Scholar 

  41. List K, Szabo R, Molinolo A, Sriuranpong V, Redeye V, Murdock T et al. Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation. Genes Dev 2005; 19: 1934–1950.

    Article  CAS  Google Scholar 

  42. Milner JM, Patel A, Davidson RK, Swingler TE, Desilets A, Young DA et al. Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis. Arthritis Rheum 2010; 62: 1955–1966.

    CAS  PubMed  Google Scholar 

  43. Lee SL, Dickson RB, Lin CY . Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease. J Biol Chem 2000; 275: 36720–36725.

    Article  CAS  Google Scholar 

  44. Suzuki M, Kobayashi H, Kanayama N, Saga Y, Suzuki M, Lin CY et al. Inhibition of tumor invasion by genomic down-regulation of matriptase through suppression of activation of receptor-bound pro-urokinase. J Biol Chem 2004; 279: 14899–14908.

    Article  CAS  Google Scholar 

  45. Uhland K . Matriptase and its putative role in cancer. Cell Mol Life Sci 2006; 63: 2968–2978.

    Article  CAS  Google Scholar 

  46. Chen CJ, Wu BY, Tsao PI, Chen CY, Wu MH, Chan YL et al. Increased matriptase zymogen activation in inflammatory skin disorders. Am J Physiol Cell Physiol 2011; 300: C406–C415.

    Article  CAS  Google Scholar 

  47. Zoratti GL, Tanabe LM, Hyland TE, Duhaime MJ, Colombo E, Leduc R et al. Matriptase regulates c-Met mediated proliferation and invasion in inflammatory breast cancer. Oncotarget 2016; 7: 58162–58173.

    Article  Google Scholar 

  48. Buchanan FG, Wang D, Bargiacchi F, DuBois RN . Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 2003; 278: 35451–35457.

    Article  CAS  Google Scholar 

  49. Li S, Ma X, Ma L, Wang C, He Y, Yu Z . Effects of ectopic HER-2/neu gene expression on the COX-2/PGE2/P450arom signaling pathway in endometrial carcinoma cells: HER-2/neu gene expression in endometrial carcinoma cells. J exp clin cancer res 2013; 32: 11.

    Article  Google Scholar 

  50. Ruder EH, Laiyemo AO, Graubard BI, Hollenbeck AR, Schatzkin A, Cross AJ . Non-steroidal anti-inflammatory drugs and colorectal cancer risk in a large, prospective cohort. Am j gastroenterol 2011; 106: 1340–1350.

    Article  CAS  Google Scholar 

  51. Cai Y, Lee YF, Li G, Liu S, Bao BY, Huang J et al. A new prostate cancer therapeutic approach: combination of androgen ablation with COX-2 inhibitor. Int J Cancer 2008; 123: 195–201.

    Article  CAS  Google Scholar 

  52. Kulp SK, Yang YT, Hung CC, Chen KF, Lai JP, Tseng PH et al. 3-phosphoinositide-dependent protein kinase-1/Akt signaling represents a major cyclooxygenase-2-independent target for celecoxib in prostate cancer cells. Cancer Res 2004; 64: 1444–1451.

    Article  CAS  Google Scholar 

  53. Jeong Y, Lee JL . Efficacy of metronomic oral cyclophosphamide with low dose dexamethasone and celecoxib in metastatic castration-resistant prostate cancer. Asia Pac J Clin Oncol 2016, epub ahead of print 12 August 2016; doi:10.1111/ajco.12583.

    Article  Google Scholar 

  54. Cheung AS, Grossmann M . COX-2 inhibitors in prostate cancer treatment—hold your horses? Asian J Androl 2012; 14: 518–519.

    Article  Google Scholar 

  55. Lam ET, Flaig TW . Prostate cancer: celecoxib trampled in the STAMPEDE trial. Nat Rev Urol 2012; 9: 358–360.

    Article  CAS  Google Scholar 

  56. Armstrong AJ . The STAMPEDE trial and celecoxib: how to adapt? Lancet Oncol 2012; 13: 443–445.

    Article  Google Scholar 

  57. Lim JT, Piazza GA, Han EK, Delohery TM, Li H, Finn TS et al. Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines. Biochem pharmacol 1999; 58: 1097–1107.

    Article  CAS  Google Scholar 

  58. Herrmann C, Block C, Geisen C, Haas K, Weber C, Winde G et al. Sulindac sulfide inhibits Ras signaling. Oncogene 1998; 17: 1769–1776.

    Article  CAS  Google Scholar 

  59. Chu TH, Chan HH, Kuo HM, Liu LF, Hu TH, Sun CK et al. Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN. Oncotarget 2014; 5: 1475–1490.

    Article  Google Scholar 

  60. Abedinpour P, Baron VT, Welsh J, Borgstrom P . Regression of prostate tumors upon combination of hormone ablation therapy and celecoxib in vivo. Prostate 2011; 71: 813–823.

    Article  CAS  Google Scholar 

  61. Igawa T, Lin FF, Lee MS, Karan D, Batra SK, Lin MF . Establishment and characterization of androgen-independent human prostate cancer LNCaP cell model. Prostate 2002; 50: 222–235.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by Taiwan National Science Council Grant NSC 100-2628-B-002-004-MY4, Ministry of Science and Technology Grants MOST 103-2321-B-002-096 and MOST 104-2320-B-002-044-MY3, National Health Research Institutes Grants NHRI-EX102-9909BC and NHRI-EX106-10401BI, and National Taiwan University Grants NTU-CESRP-104R7602C4 and NTU105R89612 to M.S. Lee, and National Taiwan University Hospital Grant NTUH106-S3387 to C.H. Chen and H.P. Huang. We thank Dr Ming-Fong Lin at the Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center for LNCaP cells, and Dr Chen-Yong Lin at the Georgetown University for his gifts of antibodies.

Author information

Author notes

  1. C-J Ko and S-W Lan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan

    C-J Ko, S-W Lan, Y-C Lu, T-S Cheng, P-F Lai, T-W Hsu, H-Y Lin, S-R Wu, H-H Lin & M-S Lee

  2. Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan

    C-H Tsai & P-W Hsiao

  3. Bureau of Investigation, Ministry of Justice, Taipei, Taiwan

    H-Y Shyu

  4. Department of Urology, National Taiwan University Hospital, Taipei, Taiwan

    C-H Chen

  5. Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan

    H-P Huang

Authors
  1. C-J Ko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S-W Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y-C Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T-S Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P-F Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C-H Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T-W Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H-Y Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H-Y Shyu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S-R Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H-H Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. P-W Hsiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. C-H Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. H-P Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M-S Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to H-P Huang or M-S Lee.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ko, CJ., Lan, SW., Lu, YC. et al. Inhibition of cyclooxygenase-2-mediated matriptase activation contributes to the suppression of prostate cancer cell motility and metastasis. Oncogene 36, 4597–4609 (2017). https://doi.org/10.1038/onc.2017.82

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.82

This article is cited by

Search

Advanced search

Quick links