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Protein-bound polysaccharide PSK inhibits tumor invasiveness by down-regulation of TGF-β1 and MMPs

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Abstract

Transforming growth factor β1 (TGF-β1) and matrix metalloproteinases (MMPs) produced by tumor cells play important roles in tumor invasion. PSK, a protein-bound polysaccharide, is widely used in Japan as an immunopotentiating biological response modifier for cancer patients. In this study, we focused on the effects of PSK on invasiveness, TGF-β1 production, and MMPs expression in two human tumor cell lines, pancreatic cancer cell line (NOR-P1) and gastric cancer cell line (MK-1P3). PSK significantly decreased the invasiveness of both cell lines through Matrigel-coated filters but did not affect cell viability, proliferation, or adhesion. Decreased invasion was associated with the inhibition of TGF-β1, MMP-2, and MMP-9 at both mRNA and protein levels as assessed by reverse transcriptase-polymerase chain reaction, gelatin zymography, and enzyme-linked immunosorbent assay. Antibody against TGF-β1 neutralized the MMP activities of both cell lines. PSK also suppressed the expression of urokinase plasminogen activator (uPA) and uPA receptor but did not change plasminogen activator inhibitor-1 (PAI-1) expression. Western blot analysis showed that PSK reduced uPA protein expression but not PAI-1 expression in the both cell lines. These results indicate that PSK suppresses tumor cell invasiveness through down-regulation of several invasion-related factors including TGF-β1, uPA, MMP-2, and MMP-9.

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References

  1. Liotta LA, Stetler-Stevenson WG. Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res (Suppl) 1991; 51: 5054–9.

    Google Scholar 

  2. Sporn MB, Roberts AB. Transforming growth factor-beta: Recent progress and new challenges. J Cell Biol 1992; 119: 1017–21.

    Article  PubMed  CAS  Google Scholar 

  3. Zhang GJ, Ladehoff D, Xu Y et al. Stable overexpression of TGFbeta 1 in a transitional carcinoma cell line: Impact on fibronectin production. J Urol 1998; 160: 230–5.

    Article  PubMed  CAS  Google Scholar 

  4. Shim KS, Kim KH, Han WS et al. Elevated serum levels of transforming growth factor-beta1 in patients with colorectal carcinoma. Cancer 1999; 85: 554–61.

    Article  PubMed  CAS  Google Scholar 

  5. Nakamura M, Katano M, Kuwahara A et al. Transforming growth factor-beta 1 (TGF-beta 1) is a preoperative prognostic indicator in advanced gastric carcinoma. Br J Cancer 1998; 78: 1373–8.

    PubMed  CAS  Google Scholar 

  6. Maehara Y, Kakeji Y, Kabashima A et al. Role of transforming growth factor-beta 1 in invasion and metastasis in gastric carcinoma. J Clin Oncol 1999; 17: 607–14.

    PubMed  CAS  Google Scholar 

  7. Albo D, Berger DH, Tuszynski GP. The effect of thrombospondin-1 and TGF-beta1 on pancreatic cancer cell invasion. J Surg Res 1998; 76: 86–90.

    Article  PubMed  CAS  Google Scholar 

  8. Kobayashi H, Ohi H, Sugimura M et al. Inhibition of in vitro ovarian cancer cell invasion by modulation of urokinase-type plasminogen activator and cathepsin B. Cancer Res 1992; 52: 3610–4.

    PubMed  CAS  Google Scholar 

  9. Tryggvason K, Hoyhtya M, Pyke C. Type IV collagenases in invasive tumors. Breast Cancer Res Treat 1993; 24: 209–18.

    Article  PubMed  CAS  Google Scholar 

  10. Samuel SK, Hurta RA, Kondaiah P et al. Autocrine induction of tumor protease production and invasion by ametallothionein-regulated TGFbeta 1 (Ser223, 225). EMBO J 1992; 11: 1599–05.

    PubMed  CAS  Google Scholar 

  11. Tsukagoshi S, Hashimoto Y, Fujii G et al. Krestin (PSK). Cancer Treat Rev 1984; 11: 131–55.

    Article  PubMed  CAS  Google Scholar 

  12. Fukushima M. Adjuvant therapy of gastric cancer: The Japanese experience. Semin Oncol 1996; 23: 369–78.

    PubMed  CAS  Google Scholar 

  13. Takahashi M, Hizuta M, Suo J et al. Antitumor effect of oral administration of PSK in tumor-bearing mice and rat. Biotherapy (Tokyo) 1992; 6: 766–8.

    Google Scholar 

  14. Mickey DD, Bencuya PS, Foulkes K. Effects of the immunomodulator PSK on growth of human prostate adenocarcinoma in immunodeficient mice. Int J Immunopharmacol 1989; 11: 829–38.

    Article  PubMed  CAS  Google Scholar 

  15. Saji S, Umemoto T, Sugiyama Y et al. Indication of immunochemotherapy using PSK for gastric cancer from the standpoint of host factors and studies of antitumor effect and PSK mechanism. Biotherapy (Tokyo) 1991; 5: 1996–04.

    Google Scholar 

  16. Sato N, Mizumoto K, Beppu K et al. Establishment of a new human pancreatic cancer cell line, NOR-P1, with high angiogenic activity and metastatic potential. Cancer Lett 2000; 155: 153–61.

    Article  PubMed  CAS  Google Scholar 

  17. Matsunaga H, Katano M, Saita T et al. Potentiation of cytotoxicity of mitomycin C by a polyacetylenic alcohol, Panaxytoriol. Cancer Chemother Pharmacol 1994; 33: 291–7.

    Article  PubMed  CAS  Google Scholar 

  18. Albini A, Iwamoto Y, Kleinman HK et al. A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res 1987; 47: 3239–45.

    PubMed  CAS  Google Scholar 

  19. Vistica DT, Skehan P, Scudiero D et al. Tetrazolium-based assays for cellular viability: A critical examination of selected parameters affecting formazan production. Cancer Res 1991; 51: 2515–20.

    PubMed  CAS  Google Scholar 

  20. Terano A, Ota S, Mach T et al. Prostaglandin protects against taurocholate-induced damage to rat gastric mucosal cell culture. Gastroenterology 1987; 92: 669–77.

    PubMed  CAS  Google Scholar 

  21. Sehgal I, Baley PA, Thompson TC. Transforming growth factor beta 1 stimulates contrasting responses in metastatic versus primary mouse prostate cancer-derived cell lines in vitro. Cancer Res 1996; 56: 3359–65.

    PubMed  CAS  Google Scholar 

  22. Chomcyzynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156–9.

    Google Scholar 

  23. O'Neil GP, Ford-Hutchinson AW. Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett 1993; 330: 156–60.

    Google Scholar 

  24. Derynck R, Jarrett JA, Chen EY et al. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature 1985; 316: 701–5.

    Article  PubMed  CAS  Google Scholar 

  25. Nagai M, Hiramatsu R, Kaneda T et al. Molecular cloning of cDNA coding for human preprourokinase. Gene 1985; 36: 183–8.

    Article  PubMed  CAS  Google Scholar 

  26. Wun TC, Kretzmer KK. cDNA cloning and expression in E. coli of a plasminogen activator inhibitor (PAI) related to a PAI produced by HepG2 hepatoma cell. FEBS Lett 1987; 210: 11–6.

    Article  PubMed  CAS  Google Scholar 

  27. Roldan AL, Cubellis MV, Masucci MT et al. Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin dependent proteolysis. EMBO J 1990; 9: 467–74.

    PubMed  CAS  Google Scholar 

  28. Schwartz GK, Wang H, Lampen N et al. Defining the invasive phenotype of proximal gastric cancer cell. Cancer 1994; 73: 22–7.

    Article  PubMed  CAS  Google Scholar 

  29. Tamarina NA, Mcmillan WD, Shively VP et al. Expression of matrix metalloproteinases and their inhibitors in aneurysms and normal aorta. Surgery 1997; 122: 264–72.

    Article  PubMed  CAS  Google Scholar 

  30. Ebina T, Murata K. Antitumor effect of intratumoral administration of a coriolus preparation, PSK: Inhibition of tumor invasion in vitro. Gan To Kagaku Ryoho 1994; 21: 2241–3.

    PubMed  CAS  Google Scholar 

  31. Kobayashi H, Matsunaga K, Oguchi Y. Antimetastatic effects of PSK (Krestin), a protein-bound polysaccharide obtained from basidiomycetes: An overview. Cancer Epidemiol Biomarkers Prev 1995; 4: 275–81.

    PubMed  CAS  Google Scholar 

  32. Matsunaga K, Ohhara M, Oguchi Y et al. Antimetastatic effect of PSK, a protein-bound polysaccharide, against the B16-BL6 mouse melanoma. Invasion Metastasis 1996; 16: 27–38.

    PubMed  CAS  Google Scholar 

  33. Katano M, Torisu M. Ambidetrous effect of PSK on motilities of both macrophages and tumor cells. Proc Am Soc Exp Biol 1980; 39: 476.

    Google Scholar 

  34. Andreasen PA, Sottrup-Jensen L, Kjoller L et al. Receptor-mediated endocytosis of plasminogen activators and activator/inhibitor complexes. FEBS Lett 1994; 338: 239–45.

    Article  PubMed  CAS  Google Scholar 

  35. Blasi F. Urokinase and urokinase receptor: a paracrine/autocrine system regulating cell migration and invasiveness. Bioassay 1993; 15: 105–11.

    Article  CAS  Google Scholar 

  36. Farina AR, Coppa A, Tiberio A et al. Transforming growth factorbeta1 enhances the invasiveness of human MDA-MB-231 breast cancer cells by upregulating urokinase activity. Int J Cancer 1998; 75: 721–30.

    Article  PubMed  CAS  Google Scholar 

  37. O'Mahony CA, Beauchamp RD, Albo D et al. Cyclooxygenase-2 alters transforming growth factor-beta 1 response during intestinal tumorigenesis. Surgery 1999; 126: 364–70.

    Article  PubMed  Google Scholar 

  38. Sehgal I, Thompson TC. Novel regulation of type IV collagenase (matrix metalloproteinase-9 and-2) activities by transforming growth factor-beta1 in human prostate cancer cell lines. Mol Biol Cell 1999; 10: 407–16.

    PubMed  CAS  Google Scholar 

  39. Harada M, Matsunaga K, Oguchi Y et al. Oral administration of PSK can improve the impaired anti-tumor CD4CT-cell response in gutassociated lymphoid tissue (GALT) of specific-pathogen-free mice. Int J Cancer 1997; 70: 362–72.

    Article  PubMed  CAS  Google Scholar 

  40. Habelhah H, Okada F, Nakai K et al. Polysaccharide K induces Mn superoxide dismutase (Mn-SOD) in tumor tissues and inhibits malignant progression of QR-32 tumor cells: Possible roles of interferon alpha, tumor necrosis factor alpha and transforming growth factor beta in Mn-SOD induction by polysaccharide K. Cancer Immunol Immunother 1998; 46: 338–44.

    Article  PubMed  CAS  Google Scholar 

  41. Matsunaga K, Hosokawa A, Oohara M et al. Direct action of a protein-bound polysacchride, PSK, on transforming growth factorbeta. Immunopharmacology 1998; 40: 219–30.

    Article  PubMed  CAS  Google Scholar 

  42. Chu TM, Kawinski E. Plasmin, substilisin-like endoproteases, tissue plasminogen activator, and urokinase plasminogen activator are involved in activation of latent TGF-beta1 in human seminal plasma. Biochem Biophys Res Comm 1998; 253: 128–34.

    Article  PubMed  CAS  Google Scholar 

  43. Nakazato H, Koike A, Saji S et al. Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Lancet 1994; 343: 1122–6.

    Article  PubMed  CAS  Google Scholar 

  44. Mitomi T, Tsuchiya S, Iijima N et al. Randomized, controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer. Dis Colon Rectum 1992; 35: 123–30.

    Article  PubMed  CAS  Google Scholar 

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Zhang, H., Morisaki, T., Matsunaga, H. et al. Protein-bound polysaccharide PSK inhibits tumor invasiveness by down-regulation of TGF-β1 and MMPs. Clin Exp Metastasis 18, 345–351 (2000). https://doi.org/10.1023/A:1010897432244

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