Skip to main content
SpringerLink
Log in

Melittin suppresses PMA-induced tumor cell invasion by inhibiting NF-κB and AP-1-dependent MMP-9 expression

  • Communication
  • Published:
Molecules and Cells

Abstract

Matrix metalloproteinase-9 (MMP-9) plays an important role in the invasion and metastasis of cancer cells. In this study, we examined the inhibitory effect of bee venom (BV) and its major peptides, melittin and apamin, on PMA-induced invasion induced by MMP-9 expression in Caki-1 renal cancer cells. BV and melittin, but not apamin, significantly suppressed PMA-induced invasion by inhibiting MMP-9 expression in Caki-1 cells. Furthermore, as evidenced by MMP-9 promoter assays, melittin inhibited MMP-9 gene expression by blocking the PMA-stimulated activations of activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB). In addition, melittin suppressed the PMA-induced phosphorylations of ERK and JNK mitogenactivated protein kinases, upstream factors involved in Ap-1 and NF-κB. These results suggest that the suppression of MMP-9 expression contributes to the anti-tumor properties of melittin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  • Benelli, R., Adatia, R., Ensoli, B., Stetler-Stevenson, W.G., Santi, L., Albini, A. (1994). Inhibition of AIDS-Kaposi’s sarcoma cell induced endothelial cell invasion by TIMP-2 and a synthetic peptide from the metalloproteinase propeptide: implications for an anti-angiogenic therapy. Oncol. Res. 6, 251–257.

    CAS  PubMed  Google Scholar 

  • Chae, Y.M., Park, K.K., Magae, J., Lee, I.S., Kim, C.H., Kim, H.C., Hong, S., Lee, J.G., Choi, I.J., Chang, Y.C., et al. (2004). Sp1-decoy oligodeoxynucleotide inhibits high glucose-induced mesangial cell proliferation. Biochem. Biophys. Res. Commun. 319, 550–555.

    Article  CAS  PubMed  Google Scholar 

  • Chambers, A.F., and Matrisian, L.M., (1997). Changing views of the role of matrix metalloproteinases in metastasis. J. Natl. Cancer Inst. 89, 260–270.

    Article  Google Scholar 

  • Cho, B.J., Im, E.K., Kwon, J.H., Lee, K.H., Shin, H.J., Oh, J., Kang, S.M., Chung, J.H., and Jang, Y. (2005). Berberine inhibits the production of lysophosphatidylcholine-induced reactive oxygen species and the ERK1/2 pathway in vascular smooth muscle cells. Mol. Cells 20, 429–434.

    CAS  PubMed  Google Scholar 

  • Cho, H.J., Kang, J.H., Kwak, J.Y., Lee, T.S., Lee, I.S., Park, N.G., Nakajima, H., Magae, J., and Chang, Y.C. (2007). Ascofuranone suppresses PMA-mediated matrix metalloproteinase-9 gene activation through the Ras/Raf/MEK/ERK- and Ap1-dependent mechanisms. Carcinogenesis 28, 1104–1110.

    Article  CAS  PubMed  Google Scholar 

  • Chu, S.T., Cheng, H.H., Huang, C.J., Chang, H.C., Chi, C.C., Su, H.H., Hsu, S.S., Wang, J.L., Chen, I.S., Jan, C.R., et al. (2007). Phospholipase A2-independent Ca2+ entry and subsequent apoptosis induced by melittin in human MG63 osteosarcoma cells. Life Sci. 80, 364–369.

    Article  CAS  PubMed  Google Scholar 

  • De Clerck, Y.A., Darville, M.I., Eeckhout, Y., and Rousseau, G.G. (1994). Characterization of the promoter of the gene encoding human tissue inhibitor of metalloproteinases-2 (TIMP-2). Gene 139, 185–191.

    Article  PubMed  Google Scholar 

  • Dempsey, C.E. (1990). The actions of melittin on membranes. Biochim. Biophys. Acta 1031, 143–161.

    CAS  PubMed  Google Scholar 

  • Eberhardt, W., Huwiler, A., Beck, K.F., Walpen, S., and Pfeilschifter, J. (2000). Amplification of IL-1 beta-induced matrix metalloproteinase 9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-kappa B and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways. J. Immunol. 165, 5788–5797.

    CAS  PubMed  Google Scholar 

  • Gevod, V.S., and Birdi, K.S. (1984). Melittin and the 8–26 fragment. Differences in ionophoric properties as measured by monolayer method. Biophys. J. 45, 1079–1083.

    Article  CAS  PubMed  Google Scholar 

  • Gum, R., Lengyel, E., Juarez, J., Chen, J.H., Sato, H., Seiki, M., and Boyd, D. (1996). Stimulation of 92-kDa gelatinase B promoter activity by ras is mitogen-activated protein kinase kinase 1-independent and requires multiple transcription factor binding sites including closely spaced PEA3/ets and AP-1 sequences. J. Biol. Chem. 271, 10672–10680.

    Article  CAS  PubMed  Google Scholar 

  • Gum, R., Wang, H., Lengyel, E., Juarez, J., and Boyd, D. (1997). Regulation of 92 kDa type IV collagenase expression by the jun aminoterminal kinase- and the extracellular signal-regulated kinase-dependent signaling cascades. Oncogene 14, 1481–1493.

    Article  CAS  PubMed  Google Scholar 

  • Hider, R.C. (1988). Honeybee venom: a rich source of pharmacologically active peptides. Endeavour 12, 60–65.

    Article  CAS  PubMed  Google Scholar 

  • Hong, S., Park, K.K., Magae, J., Ando, K., Lee, T.S., Kwon, T.K., Kwak, J.Y., Kim, C.H., and Chang, Y.C. (2005). Ascochlorin inhibits matrix metalloproteinase-9 expression by suppressing activator protein-1-mediated gene expression through the ERK1/2 signaling pathway: inhibitory effects of ascochlorin on the invasion of renal carcinoma cells. J. Biol. Chem. 280, 25202–25209.

    Article  CAS  PubMed  Google Scholar 

  • Jang, M.H., Shin, M.C., Lim, S., Han, S.M., Park, H.J., Shin, I., Lee, J.S., Kim, K.A., Kim, E.H., and Kim, C.J. (2003). Bee venom induces apoptosis and inhibits expression of cyclooxygenase-2 mRNA in human lung cancer cell line NCI-H1299. J. Pharmacol. Sci. 91, 95–104.

    Article  CAS  PubMed  Google Scholar 

  • Kohler, M., Hirschberg, B., Bond, C.T., Kinzie, J.M., Marrion, N.V., Maylie, J., and Adelman, J.P. (1996). Small-conductance, calcium-activated potassium channels from mammalian brain. Science 273, 1709–1714.

    Article  CAS  PubMed  Google Scholar 

  • Kwon, Y.B., Lee, J.D., Lee, H.J., Han, H.J., Mar, W.C., Kang, S.K., Beitz, A.J., and Lee, J.H. (2001). Bee venom injection into an acupuncture point reduces arthritis associated edema and nociceptive responses. Pain 90, 271–280.

    Article  CAS  PubMed  Google Scholar 

  • Kwon, Y.B., Lee, H.J., Han, H.J., Mar, W.C., Kang, S.K., Yoon, O.B., Beitz, A.J., and Lee, J.H. (2002). The water-soluble fraction of bee venom produces antinociceptive and anti-inflammatory effects on rheumatoid arthritis in rats. Life Sci. 71, 191–204.

    Article  CAS  PubMed  Google Scholar 

  • Lakka, S.S., Gondi, C.S., Yanamandra, N., Olivero, W.C., Dinh, D.H., Gujrati, M., and Rao, J.S. (2004). Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis. Oncogene 23, 4681–4689.

    Article  CAS  PubMed  Google Scholar 

  • Lee, S.J., Sakurai, H., Oshima, K., Kim, S.H., and Saiki, I. (2003). Anti-metastatic and anti-angiogenic activities of a new matrix metalloproteinase inhibitor, TN-6b. Eur. J. Cancer 39, 1632–1641.

    Article  CAS  PubMed  Google Scholar 

  • Lee, S.O., Jeong, Y.J., Im, H.G., Kim, C.H., Chang, Y.C., and Lee, I.S. (2007). Silibinin suppresses PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7 human breast carcinoma cells. Biochem. Biophys. Res. Commun. 354, 165–171.

    Article  CAS  PubMed  Google Scholar 

  • Lein, M., Jung, K., Laube, C., Hubner, T., Winkelmann, B., Stephan, C., Hauptmann, S., Rudolph, B., Schnorr, D., and Loening, S.A. (2000). Matrix-metalloproteinases and their inhibitors in plasma and tumor tissue of patients with renal cell carcinoma. Int. J. Cancer 85, 801–804.

    Article  CAS  PubMed  Google Scholar 

  • Lin, C.W., Hou, W.C., Shen, S.C., Juan, S.H., Ko, C.H., Wang, L.M., and Chen, Y.C. (2008). Quercetin inhibition of tumor invasion via suppressing PKC delta/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis 29, 1807–1815.

    Article  CAS  PubMed  Google Scholar 

  • Moon, D.O., Park, S.Y., Heo, M.S., Kim, K.C., Park, C., Ko, W.S., Choi, Y.H., and Kim, G.Y. (2006). Key regulators in bee venominduced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt. Int. Immunopharmacol. 6, 1796–1807.

    Article  CAS  PubMed  Google Scholar 

  • Moon, D.O., Park, S.Y., Choi, Y.H., Kim, N.D., Lee, C., and Kim, G.Y. (2008). Melittin induces Bcl-2 and caspase-3-dependent apoptosis through downregulation of Akt phosphorylation in human leukemic U937 cells. Toxicon 51, 112–120.

    Article  CAS  PubMed  Google Scholar 

  • Nabeshima, K., Inoue, T., Shimao, Y., and Sameshima, T. (2002). Matrix metalloproteinases in tumor invasion: role for cell migration. Pathol. Int. 52, 255–264.

    Article  CAS  PubMed  Google Scholar 

  • Nah, S.S., Ha, E., Lee, H.J., and Chung, J.H. (2007). Inhibitory effects of melittin on the production of lipopolysaccharideinduced matrix metalloproteinase 3 in human osteoarthritic chondrocytes. Toxicon 49, 881–885.

    Article  CAS  PubMed  Google Scholar 

  • Nakshatri, H., Bhat-Nakshatri, P., Martin, D.A., Goulet, Jr. R.J., and Sledge, Jr. G.W. (1997). Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol. Cell. Biol. 17, 3629–3639.

    CAS  PubMed  Google Scholar 

  • Orsolic, N., Sver, L., Verstovsek, S., Terzic, S., and Basic, I. (2003). Inhibition of mammary carcinoma cell proliferation in vitro and tumor growth in vivo by bee venom. Toxicon 41, 861–870.

    Article  CAS  PubMed  Google Scholar 

  • Park, D., Shim, E., Kim, Y., Kim, Y.M., Lee, H., Choe, J., Kang, D., Lee, YS., and Jeoung, D. (2008). C-FLIP promotes the motility of cancer cells by activating FAK and ERK, and increasing MMP-9 expression. Mol. Cells 25, 184–195.

    CAS  PubMed  Google Scholar 

  • Ray, J.M., and Stetler-Stevenson, W.G. (1994). The role of matrix metalloproteases and their inhibitors in tumour invasion, metastasis and angiogenesis. Eur. Respir. J. 7, 2062–2072.

    CAS  PubMed  Google Scholar 

  • Sato, H., and Seiki, M. (1993). Regulatory mechanism of 92 kDa type IV collagenase gene expression which is associated with invasiveness of tumor cells. Oncogene 8, 395–405.

    CAS  PubMed  Google Scholar 

  • Shishodia, S., Majumdar, S., Banerjee, S., and Aggarwal, B.B. (2003). Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of Ikappa-Balpha kinase and p65 phosphorylation: correlation with downregulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res. 63, 4375–4383.

    CAS  PubMed  Google Scholar 

  • Simon, C., Goepfert, H., and Boyd, D. (1998). Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion. Cancer Res. 58, 1135–1139.

    CAS  PubMed  Google Scholar 

  • Son, Y.O., Lee, K.Y., Choi, K.C., Chung, Y., Kim, J.G., Jeon, Y.M., Jang, Y.S., and Lee, J.C. (2004). Inhibitory effects of glycoprotein-120 (G-120) from Ulmus davidiana Nakai on cell growth and activation of matrix metalloproteinases. Mol. Cells 18, 163–170.

    CAS  PubMed  Google Scholar 

  • Son, D.J., Ha, S.J., Song, H.S., Lim, Y., Yun, Y.P., Lee, J.W., Moon, D.C., Park, Y.H., Park, B.S., Hong, J.T., et al. (2006). Melittin inhibits vascular smooth muscle cell proliferation through induction of apoptosis via suppression of nuclear factor-kappaB and Akt activation and enhancement of apoptotic protein expression. J. Pharmacol. Exp. Ther. 317, 627–634.

    Article  CAS  PubMed  Google Scholar 

  • Son, D.J., Lee, J.W., Lee, Y.H., Song, H.S., Lee, C.K., and Hong, J.T. (2007). Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds. Pharmacol. Ther. 115, 246–270.

    Article  CAS  PubMed  Google Scholar 

  • Stetler-Stevenson, W.G., Brown, P.D., Onisto, M., Levy, A.T., and Liotta, L.A. (1990). Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. J. Biol. Chem. 265, 13933–13938.

    CAS  PubMed  Google Scholar 

  • Stetler-Stevenson, W.G., Hewitt, R., and Corcoran, M. (1996). Matrix metalloproteinases and tumor invasion: from correlation and causality to the clinic. Semin. Cancer Biol. 7, 147–154.

    Article  CAS  PubMed  Google Scholar 

  • Wang, C., Chen, T., Zhang, N., Yang, M., Li, B., Lü, X., Cao, X., and Ling, C. (2009). Melittin, a major component of bee venom, sensitizes human hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating CaMKII-TAK1-JNK/p38 and inhibiting IkappaBalpha kinase-NFkappaB. J. Biol. Chem. 284, 3804–3813.

    Article  CAS  PubMed  Google Scholar 

  • Woo, M.S., Jung, S.H., Kim, S.Y., Hyun, J.W., Ko, K.H., Kim, W.K., and Kim, H.S. (2005). Curcumin suppresses phorbol esterinduced matrix metalloproteinase-9 expression by inhibiting the PKC to MAPK signaling pathways in human astroglioma cells. Biochem. Biophys. Res. 335, 1017–1025.

    Article  CAS  Google Scholar 

  • Zucker, S., Lysik, R.M., Zarrabi, M.H., and Moll, U. (1993). M(r) 92,000 type IV collagenase is increased in plasma of patients with colon cancer and breast cancer. Cancer Res. 53, 140–146.

    CAS  PubMed  Google Scholar 

  • Zucker, S., Cao, J., and Chen, W.T. (2000). Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene 19, 6642–6650.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu, 705-718, Korea

    Yun-Jeong Jeong, Kwan-Kyu Park, Hyun-Ji Cho & Young-Chae Chang

  2. Department of Rehabilitation Medicine, Eulji University Hospital, Daejeon, 302-799, Korea

    Jung Hyun Park

  3. Department of Biotechnology, Catholic University of Daegu, Gyeongsan, 712-702, Korea

    Il-Kyung Chung

  4. Animal Biotechnology, Graduate School of Bio., and Information Technology, Hankyong National University, Anseong, 456-749, Korea

    Kwan-Sik Min

  5. Department of Physical Therapy, Inje University, Gimhae, 621-749, Korea

    Mihyun Kim

  6. Department of Agricultural Biology, National Institute of Agricultural Science and Technology, Suwon, 441-100, Korea

    Kwang-Gill Lee & Joo-Hong Yeo

  7. Department of Oral Biology, College of Dentistry, Yonsei University, Seoul, 120-752, Korea

    Kwang-Kyun Park

Authors
  1. Jung Hyun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yun-Jeong Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kwan-Kyu Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyun-Ji Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Il-Kyung Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kwan-Sik Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mihyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kwang-Gill Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joo-Hong Yeo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kwang-Kyun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Young-Chae Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Young-Chae Chang.

About this article

Cite this article

Park, J.H., Jeong, YJ., Park, KK. et al. Melittin suppresses PMA-induced tumor cell invasion by inhibiting NF-κB and AP-1-dependent MMP-9 expression. Mol Cells 29, 209–215 (2010). https://doi.org/10.1007/s10059-010-0028-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10059-010-0028-9

Keywords

Search

Navigation