Biophytum sensitivum (L.) DC Inhibits Tumor Cell Invasion and Metastasis Through a Mechanism Involving Regulation of MMPs,Prolyl Hydroxylase,Lysyl Oxidase,nm23,ERK-1,ERK-2,STAT-1,and Proinflammatory Cytokine Gene Expression in Metastatic Lung Tissue
Free accessResearch articleFirst published online March, 2008
Biophytum sensitivum (L.) DC Inhibits Tumor Cell Invasion and Metastasis Through a Mechanism Involving Regulation of MMPs,Prolyl Hydroxylase,Lysyl Oxidase,nm23,ERK-1,ERK-2,STAT-1,and Proinflammatory Cytokine Gene Expression in Metastatic Lung Tissue
Biophytum sensitivum is a traditional oriental herbal medicine that is known for its immunostimulatory and antitumor effects. Tumor metastasis is the most important cause of cancer death. Although B sensitivum was shown to inhibit metastasis, the mechanism underlying this action is not well understood. In the present report, the authors had studied the effect of B sensitivum on the invasion and motility of B16F-10 melanoma cells and investigate the regulatory effect on the expression of matrix metalloproteases (MMPs), prolyl hydoxylase, lysyl oxidase, nm23, extracellular signal-regulated kinase (ERK)—1, ERK-2, signal transducer and activator of transcription (STAT)—1, and proinflammatory cytokines in metastatic tumor-bearing lungs. B sensitivum inhibited the invasion and motility of B16F-10 cells in a dose-dependent manner. B sensitivum inhibited the expression of MMP-2 and MMP-9, whereas it activated STAT-1 expression in metastatic tumor-bearing lungs. Similarly, inhibition of prolyl hydroxylase, lysyl oxidase, ERK-1, ERK-2, and vascular endothelial growth factor (VEGF) expression but activation of nm23 by B sensitivum was observed in metastatic tumor-bearing lungs. B sensitivum treatment also downregulated the expression of tumor necrosis factor—α, interleukin (IL)—1β, IL-6, and granulocyte monocyte—colony stimulating factor in metastatic tumor-bearing lungs. In B16F-10 cells, B sensitivum also inhibited the production of proinflammatory cytokines. Overall, the results indicate that B sensitivum exhibits antimetastatic effects through the inhibition of invasion and motility. The results also suggest that MMPs, prolyl hydroxylase, lysyl oxidase, nm23, ERKs, VEGF, STAT, and proinflammatory cytokines are critical regulators of the B sensitivum—mediated antimetastatic effect.
Fidler IJ, Gersten DM, Hart IRThe biology of cancer invasion and metastasis. Adv Cancer Res. 1978;28:149-250.
2.
Liotta L., Rao CN, Barsky SHTumor invasion and the extracellular matrix. Lab Invest . 1983;49:636-649.
3.
Puri D.The insulinotropic activity of the Nepalese medicinal plant Biophytum sensitivum, preliminary experimental study. J Ethnopharmacol . 2001;78:89-93.
4.
Jachak SM, Bucar F., Kartnig T.Antiinflammatory activity of Biophytum sensitivum in carrageenin induced rat paw oedema. Phytother Res. 1999;13:73-74.
5.
Lin YL, Wang WYChemical constituents of Biophytum sensitivum. Chin Pharm . 2003;55:71-75.
6.
Guruvayoorappan C., Afira AH, Kuttan G.Antioxidant potential of Biophytum sensitivum extract in vitro and in vivo. J Basic Clin Physiol Pharmacol . 2006;17:255-267.
7.
Guruvayoorappan C., Kuttan G.Immunomodulatory and antitumor activity of Biophytum sensitivum extract. Asian Pacific J Cancer Prev . 2007;8:27-32.
8.
Guruvayoorappan C., Kuttan G.Anti-angiogenic effect of Biophytum sensitivum is exerted through its cytokine modulation activity and inhibitory activity against VEGF mRNA expression, endothelial cell migration and capillary tube formation. J Exp Ther Oncol. 2007;6:241-250.
9.
Guruvayoorappan C., Kuttan G.Anti-metastatic effect of Biophytum sensitivum is exerted through its cytokine and immunomodulatory activity and its regulatory effect on the activation and nuclear translocation of transcription factors in B16F-10 melanoma cells. J Exp Ther Oncol. In press.
10.
Sunila ES, Kuttan G.A preliminary study on antimetastatic activity of Thuja occidentalis L. in mice model. Immunopharmacol Immunotoxicol.2006;18:269-280.
11.
Albini A., Iwamoto Y., Kleinman HK, et al. A rapid in vitro assay quantitating the invasive potential of tumor cells. Cancer Res.1987;47:3239-3245.
12.
Liabakk NB, Talbot I., Smith RA, Wilkinson K., Balkwill F.Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res. 1996;56:190.
13.
Koshiba T., Hosotani R., Wada M., et al. Involvement of matrix metalloproteinase-2 activity in invasion and metastasis of pancreatic carcinoma. Cancer. 1998;82:642.
14.
Kohno M., Pouyssegur J.Pharmacological inhibitors of the ERK signaling pathway: application as anticancer drugs. Progress Cell Cycle Res. 2003;5:219-224.
15.
Colomer R.Gemcitabine and paclitaxel in metastatic breast cancer. Oncology . 2004;18:8-12.
16.
Menon LG, Kuttan R., Kuttan G.Antimetastatic activity of cur-cumin and catechin. Cancer Lett. 1999;141:159-165.
17.
Liotta LA, Stetler-Stevenson WG, Steeg PSCancer invasion and metastasis: positive and negative regulatory elements . Cancer Invest. 1991;9:543-551.
18.
Cavallaro U. , Christofori G.Cell adhesion in tumor invasion and metastasis: loss of the glue is not enough. Biochim Biophys Acta. 2001;1551:39-45.
19.
Bernhard EJ , Gruber SB, Muschel RJDirect evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/ collagenase) to the metastatic phenotype in transformed rat embryo cells. Proc Natl Acad Sci U S A . 1994;91:4293-4297.
20.
Heppner KJ, Matrisian LM, Jensen RA, Rodgers WHExpression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol . 1996;149:273-282.
21.
Basset P., Okada A., Chenard MP, et al, Matrix metalloproteinases as stromal effectors of human carcinoma progression: therapeutic implications. Matrix Biol.1997;15:535-541.
22.
Johnsen M., Lund LR, Romer J., Almholt K., Dano D.Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation. Curr Opin Cell Biol. 1998 ;10:667-671.
23.
Huang S., Bucana CD, Van Arsdall M., Fidler IJStat 1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells. Oncogene. 2002;21:2504-2512.
24.
Gil MP, Bohn E., O'Guin AK, et al. Biological consequences of Stat1-independent IFN signaling. Proc Natl Acad Sci U S A. 2001;98:6680-6685.
25.
Ramana CV, Gil MP, Han Y., Ransohoff KM, Schreiber RD, Stark GRStat1-independent regulation of gene expression in response to IFN-gamma . Proc Natl Acad Sci U S A. 2001;98:6674-6679.
26.
Chin YE, Kitagawa M., Kuida K., Flavell RA, Fu XYActivation of STAT signaling pathway can cause the expression of caspase 1 and apoptosis. Mol Cell Biol. 1997;9:5328-5337.
27.
Kumar A., Commane M., Flickinger TW, Horvath CM, Stark GR. Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science. 1997;278:1630-1632.
28.
Guruvayoorappan C., Kuttan G.Effect of Biophytum sensitivum on cell mediated immune response in mice. Immunopharmacol Immunotoxicol. 2007;29:337-350.
29.
Lewis TS, Shapiro PS, Ahn NGSignal transduction through MAP kinase cascades. Adv Cancer Res.1998;74:49-139.
30.
Pearson G., Robinson F., Gibson TB, et al. Mitogen activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001 ;22:153-183.
31.
Sebolt-Leoopold JS, Dudley DT, Herrara R., et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med.1999;5:810-816.
32.
Knockaert M. , Lenormand P., Baffet G., et al. p42/p44 MAPKs are intracellular targets of CDK inhibitor purvalanol. Oncogene . 2002 ;21:6413-6424.
33.
Carmeliet P. , Jain RKAngiogenesis in cancer and other diseases . Nature. 2000;407:249-257.
34.
Milanini-Mongiat J., Pouyssegur J., Pages G.Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription. J Biol Chem. 2002;277:20631-20639.
35.
Steeg PS, Bevilacqua G., Pozzatti R., Liotta LA, Sobel MEAltered expression of NM23, a gene associated with low tumor metastatic potential, during Adenovirus 2 Ela inhibition of experimental metastasis. Cancer Res. 1988;48:6550-6554.
36.
Fujimoto Y. , Ohtake T., Nishimori H., et al. Reduced expression and rare genomic alteration of nm23-H1 in human hepatocellular carcinoma and hepatoma cell lines. J Gastroenterol.1998 ;33:368-375.
37.
Iizuka N., Oka M., Noma T., Nakazawa A., Hirose K., Suzuki T.NM23-H1 and NM23-H2 messenger RNA abundance in human hepatocellular carcinoma . Cancer Res. 1995;55:652-657.
38.
Smith-Mungo LI, Kagan HMLysyl oxidase: properties, regulation and multiple functions in biology. Matrix Biol. 1998; 16:387-398.
39.
Akiri G., Sabo E., Dafni H., et al. Lysyl oxidase protein-1 promotes tumor fibrosis and tumor progression in vivo. Cancer Res.2003;63:1657-1666.
40.
Kirschmann DA, Seftor EA, Fong SF, et al. A molecular role of lysyl oxidase in breast cancer invasion. Cancer Res.2002 ;62:4478-4483.
41.
Giampuzzi M. , Oleggini R., Albanese C., Pestell R., Di Donato A.β-catenin signaling and regulation of cyclin D1 promoter in NRK-49F cells transformed by down-regulation of the tumor suppressor lysyl oxidase. Biochim Biophys Acta. 2005;1745: 370-381.
42.
Fahling M., Perlewitz A., Doller A., Thiele BJRegulation of collagen prolyl 4-hydroxylase and matrix metalloproteinases in fibrosarcoma cells by hypoxia. Comp Biochem Physiol Part C. 2004;139:119-126.
43.
Ivan M., Kondo K., Yang H., et al. HIFα targeted for VHL-mediated destruction of proline hydroxylation: implications for O2 sensing. Science. 2001 ;292:464-468.
44.
Jaakkola P. , Mole DR, Tian YM, et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation . Science. 2001;292:468-472.
45.
Lazar-Moinar E., Toth S., Falus A.Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine . 2000;12:547-554.
46.
Dong G., Chen Z., Kato T., Van Waes C.The host environment promotes the constitutive activation of nuclear factor-kappa B and proinflammatory cytokine expression during metastatic tumor progression of murine squamous cell carcinoma. Cancer Res . 1999;59:3495-3504.
47.
Chen Z., Malhotra PS, Thomas GR, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res.1999;5: 1369-1379.
