α-Mangostin Suppresses Phorbol 12-myristate 13-acetate-Induced MMP-2/MMP-9 Expressions via αvβ3 Integrin/FAK/ERK and NF-κB Signaling Pathway in Human Lung Adenocarcinoma A549 Cells

Abstract

The purpose of this study is to investigate the anti-metastatic effect of α-mangostin on phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) expressions in A549 human lung adenocarcinoma cells. Firstly, α-mangostin could inhibit PMA-induced abilities of the adhesion, invasion, and migration. Data also showed α-mangostin could inhibit the activation of αvβ3 integrin, focal adhesion kinase (FAK), and extracellular signal-regulated kinase1/2 (ERK1/2) involved in the downregulation the enzyme activities, protein and messenger RNA levels of MMP-2 and MMP-9 induced by PMA. Next, α-mangostin also strongly inhibited PMA-induced degradation of inhibitor of kappaBα (IκBα) and the nuclear levels of nuclear factor kappa B (NF-κB). Also, a dose-dependent inhibition on the binding abilities of NF-κB by α-mangostin treatment was further observed. Furthermore, reduction of FAK or ERK1/2 phosphorylation by FAK small interfering RNA (FAK siRNA) potentiated the effect of α-mangostin. Finally, the transient transfection of ERK siRNA significantly down-regulated the expressions of MMP-2 and MMP-9 concomitantly with a marked inhibition on cell invasion and migration. Presented results indicated α-mangostin is a novel, effect, anti-metastatic agent that functions by downregulating MMP-2 and MMP-9 gene expressions.

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Abbreviations

PMA:

Phorbol 12-myristate 13-acetate

MMPs:

Matrix metalloproteinases

ECM:

Extracellular matrix

ERK:

Extracellular signaling-regulating kinase

JNK/SAPK:

c-Jun N-terminal kinase/stress-activated protein kinase

p38 MAPK:

p38 Mitogen-activated protein kinase

PI3K/Akt:

Phosphoinositide 3-kinase/protein kinase B

NF-κB:

Nuclear factor kappa B

IκBα:

Inhibitor of NF-κB

References

  1. 1.

    Greenlee, R. T., Hill-Harmon, M. B., Murraym, T., & Thunm, M. (2001). Cancer statistics. CA: A Cancer Journal for Clinicians, 51, 15–36.

    Article  CAS  Google Scholar 

  2. 2.

    Gupta, G. P., & Massague, J. (2006). Cancer metastasis: building a framework. Cell, 127, 679–695.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Jemal, A., Murray, T., Ward, E., Samuels, A., Tiwari, R. C., Ghafoor, A., et al. (2005). Cancer statistics, 2005. CA: A Cancer Journal for Clinicians, 55, 10–30.

    Article  Google Scholar 

  4. 4.

    Jung, H. A., Su, B. N., Keller, W. J., Mehta, R. G., & Kinghorn, A. D. (2006). Antioxidant xanthones from the pericarp of Garcinia mangostana (Mangosteen). Journal of Agriculture and Food Chemistry, 54, 2077–2082.

    Article  CAS  Google Scholar 

  5. 5.

    Fu, C., Loo, A. E., Chia, F. P., & Huang, D. (2007). Oligomeric proanthocyanidins from mangosteen pericarps. Journal of Agriculture and Food Chemistry, 55, 7689–7694.

    Article  CAS  Google Scholar 

  6. 6.

    Peres, V., & Nagem, T. J. (1997). Trioxygenated naturally occurring xanthones. Phytochemistry, 44, 191–214.

    Article  CAS  Google Scholar 

  7. 7.

    Jinsart, W., Ternai, B., Buddhasukh, D., & Polya, G. M. (1992). Inhibition of wheat embryo calcium-dependent protein kinase and other kinases by mangostin and γ-mangostin. Phytochemistry, 31, 3711–3713.

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Chairungsrilerd, N., Furukawa, K. I., Ohta, T., Nozoe, S., & Ohizumi, Y. (1996). Pharmacological properties of α-mangostin, a novel histamine H1 receptor antagonist. European Journal of Pharmacology, 314, 351–356.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Ho, C. K., Huang, Y. L., & Chen, C. C. (2002). Garcinone E, a xanthone derivative, has potent cytotoxic effect against hepatocellular carcinoma cell lines. Planta Medica, 68, 975–979.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Moongkarndi, P., Kosem, N., & Kaslungka, S. (2004). Antiproliferation, antioxidation and induction of apoptosis by Garcinia mangostana (mangosteen) on SKBR3 human breast cancer cell line. Journal of Ethnopharmacology, 90, 161–166.

    Article  PubMed  Google Scholar 

  11. 11.

    Nakagawa, Y., Iinuma, M., Naoe, T., Nozawa, Y., & Akao, Y. (2007). Characterized mechanism of alpha-mangostin-induced cell death: caspase-independent apoptosis with release of endonuclease-G from mitochondria and increased miR-143 expression in human colorectal cancer DLD-1 cells. Bioorganic & Medicinal Chemistry, 15, 5620–5628.

    Article  CAS  Google Scholar 

  12. 12.

    Hung, S. H., Shen, K. H., Wu, C. H., Liu, C. L., & Shih, Y. W. (2009). α-Mangostin suppresses PC-3 human prostate carcinoma cell metastasis by inhibiting matrix metalloproteinase-2/9 and urokinase-plasminogen activator expression through the JNK signaling pathway. Journal of Agriculture and Food Chemistry, 57, 1291–1298.

    Article  CAS  Google Scholar 

  13. 13.

    Woodhouse, E. C., Chuaqui, R. F., & Liotta, L. A. (1997). General mechanisms of metastasis. Cancer, 180, 1529–1537.

    Article  Google Scholar 

  14. 14.

    Humphries, M. J. (2000). Integrin structure. Biochemical Society Transactions, 28, 311–339.

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Stupack, D. G. (2007). The biology of integrins. Oncology, 21, 6–12.

    PubMed  Google Scholar 

  16. 16.

    van Nimwegen, M. J., & van de Water, B. (2007). Focal adhesion kinase: A potential target in cancer therapy. Biochemical Pharmacology, 73, 597–609.

    Article  PubMed  Google Scholar 

  17. 17.

    Mitra, S. K., & Schlaepfer, D. D. (2006). Integrin-regulated FAK-Src signaling in normal and cancer cells. Current Opinion in Cell Biology, 18, 516–523.

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Lauffenburger, D. A., & Horwitz, A. F. (1996). Cell migration: A physically integrated molecular process. Cell, 84, 359–369.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Siesser, P. M., & Hanks, S. K. (2006). The signaling and biological implications of FAK over-expression in cancer. Clinical Cancer Research, 12, 3233–3237.

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Cary, L. A., Han, D. C., Polte, T. R., Hanks, S. K., & Guan, J. L. (1998). Identification of p130Cas as a mediator of focal adhesion kinase-promoted cell migration. The Journal of Cell Biology, 140, 211–221.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Klemke, R. L., Cai, S., Giannini, A. L., Gallagher, P. J., de Lanerolle, P., & Cheresh, D. A. (1997). Regulation of cell motility by mitogen-activated protein kinase. The Journal of Cell Biology, 137, 481–492.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Klemke, R. L., Leng, J., Molander, R., Brooks, P. C., Vuori, K., & Cheresh, D. A. (1998). CAS/Crk coupling serves as a “molecular switch” for induction of cell migration. The Journal of Cell Biology, 140, 961–972.

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Zheng, D. Q., Woodard, A. S., Tallini, G., & Languino, L. R. (2000). Substrate specificity of alpha vbeta 3 integrin-mediated cell migration and phosphatidylinositol 3-kinase/AKT pathway activation. The Journal of Biological Chemistry, 275, 24565–24574.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Szallasi, A., & Blumberg, P. M. (1990). Effect of resiniferatoxin pretreatment on the inflammatory response to phorbol-12-myristate-13-acetate in mouse strains with different susceptibilities to phorbol ester tumor promotion. Carcinogenesis, 11, 583–587.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Fåhraeus, R., & Lane, D. P. (1999). The p16 (INK4a) tumour suppressor protein inhibits alphavbeta3 integrin-mediated cell spreading on vitronectin by blocking PKC-dependent localization of alphavbeta3 to focal contacts. The EMBO Journal, 18, 2106–2118.

    Article  PubMed  Google Scholar 

  26. 26.

    Shannon, K. E., Keene, J. L., & Settle, S. L. (2004). Anti-metastatic properties of RGD peptide-mimetic agents S137 and S247. Clinical & Experimental Metastasis, 21, 129–138.

    Article  CAS  Google Scholar 

  27. 27.

    Eliceiri, B. P., Puente, X. S., Hood, J. D., Stupack, D. G., Schlaepfer, D. D., Huang, X. Z., et al. (2002). Src-mediated coupling of focal adhesion kinase to integrin alpha(v)beta5 in vascular endothelial growth factor signaling. The Journal of Cell Biology, 157, 149–159.

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Mason, C. K., McFarlane, S., Johnston, P. G., Crowe, P., Erwin, P. J., Domostoj, M. M., et al. (2008). Agelastatin A: A novel inhibitor of osteopontin-mediated adhesion, invasion, and colony formation. Molecular Cancer Therapeutics, 7, 548–558.

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Suzuki, M., Mose, E., Galloy, C., & Tarin, D. (2007). Osteopontin gene expression determines spontaneous metastatic performance of orthotopic human breast cancer xenografts. The American Journal of Pathology, 171, 682–692.

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    El-Tanani, M. K. (2008). Role of osteopontin in cellular signaling and metastatic phenotype. Frontiers in Bioscience, 13, 4276–4284.

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Huang, Q., Shen, H. M., & Ong, C. N. (2004). Inhibitory effect of emodin on tumor invasion through suppression of activator protein-1 and nuclear factor-kappaB. Biochemical Pharmacology, 68, 361–371.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Huang, S. C., Ho, C. T., Lin-Shiau, S. Y., & Lin, J. K. (2005). Carnosol inhibits the invasion of B16/F10 mouse melanoma cells by suppressing metalloproteinase-9 through down-regulating nuclear factor-kappa B and c-Jun. Biochemical Pharmacology, 69, 221–232.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Bernhard, E. J., Gruber, S. B., & Muschel, R. J. (1994). Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. Proceedings of the National Academy of Sciences of the United States of America, 91, 4293–4297.

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Chen, Y. C., Shen, S. C., & Tsai, S. H. (2005). Prostaglandin D(2) and J(2) induce apoptosis in human leukemia cells via activation of the caspase 3 cascade and production of reactive oxygen species. Biochimica et Biophysica Acta, 1743, 291–304.

    CAS  PubMed  Google Scholar 

  35. 35.

    Jang, B. C., Park, Y. K., Choi, I. H., Kim, S. P., Hwang, J. B., Baek, W. K., et al. (2007). 12-O-tetradecanoyl phorbol 13-acetate induces the expression of B7-DC, -H1, -H2, and -H3 in K562 cells. International Journal of Oncology, 31, 1439–1447.

    CAS  PubMed  Google Scholar 

  36. 36.

    Carpenter, C. L., & Cantley, L. C. (1996). Phosphoinositide kinases. Current Opinion in Cell Biology, 8, 153–158.

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Chung, T. W., Lee, Y. C., & Kim, C. H. (2004). Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. The FASEB Journal, 18, 1123–1125.

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65, 55–63.

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Ochi, Y., Atsumi, S., Aoyagi, T., & Umezawa, K. (1993). Inhibition of tumor cell invasion in the Boyden chamber assay by a mannosidase inhibitor, mannostatin A. Anticancer Research, 13, 1421–1424.

    CAS  PubMed  Google Scholar 

  40. 40.

    Hoppe-Seyler, F., Butz, K., Rittmuller, C., & von Knebel Doeberitz, M. (1991). A rapid microscale procedure for the simultaneous preparation of cytoplasmic RNA, nuclear DNA binding proteins and enzymatically active luciferase extracts. Nucleic Acids Research, 19, 5080.

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Ma, W., Lim, W., Gee, K., Aucoin, S., Nandan, D., Kozlowski, M., et al. (2001). The p38 mitogen-activated kinase pathway regulates the human interleukin-10 promoter via the activation of Sp1 transcription factor in lipopolysaccharide stimulated human macrophages. The Journal of Biological Chemistry, 276, 13664–13674.

    CAS  PubMed  Google Scholar 

  42. 42.

    Pfaff, M., Tangemann, K., Müller, B., Gurrath, M., Müller, G., Kessler, H., et al. (1994). Selective recognition of cyclic RGD peptides of NMR defined conformation by alpha IIb beta 3, alpha V beta 3, and alpha 5 beta 1 integrins. The Journal of Biological Chemistry, 269, 20233–20238.

    CAS  PubMed  Google Scholar 

  43. 43.

    Surh, Y. J., Chun, K. S., Cha, H. H., Han, S. S., Keum, Y. S., Park, K. K., et al. (2001). Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutation Research, 480–481, 243–268.

    PubMed  Google Scholar 

  44. 44.

    Bharti, A. C., & Aggarwal, B. B. (2002). Nuclear factor-kappa B and cancer: Its role in prevention and therapy. Biochemical Pharmacology, 64, 883–888.

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Brockman, J. A., Scherer, D. C., McKinsey, T. A., Hall, S. M., Qi, X., Lee, W. Y., et al. (1995). Coupling of a signal response domain in IkBa to multiple pathways for NF-kB activation. Molecular and Cellular Biology, 15, 2809–2818.

    CAS  PubMed  Google Scholar 

  46. 46.

    Sundaram, B. M., Gopalakrishnan, C., Subramanian, S., Shankaranarayanan, D., & Kameswaran, L. (1983). Antimicrobial activities of Garcinia mangostana. Planta Medica, 48, 59–60.

    Article  Google Scholar 

  47. 47.

    Nabandith, V., Suzui, M., Morioka, T., Kaneshiro, T., Kinjo, T., Matsumoto, K., et al. (2004). Inhibitory effects of crude alpha-mangostin, a xanthone derivative, on two different categories of colon preneoplastic lesions induced by 1,2-dimethylhydrazine in the rat. Asian Pacific Journal of Cancer Prevention, 5, 433–438.

    PubMed  Google Scholar 

  48. 48.

    Shihm, Y. W., Chenm, P. S., Wum, C. H., Jengm, Y. F., & Wang, C. J. (2007). α-Chaconine-reduced metastasis involves a PI3K/Akt signaling pathway with downregulation of NF-κB in human lung adenocarcinoma A549 cells. Journal of Agriculture and Food Chemistry, 55, 11035–11043.

    Article  Google Scholar 

  49. 49.

    Miranti, C. K., & Bruggem, J. S. (2002). Sensing the environment: A historical perspective on integrin signal transduction. Nature Cell Biology, 4, E83–E90.

    Article  CAS  PubMed  Google Scholar 

  50. 50.

    Kapur, S., Baylink, D. J., & Lau, K. H. (2003). Fluid flow shear stress stimulates human osteoblast proliferation and differentiation through multiple interacting and competing signal transduction pathways. Bone, 32, 241–251.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Li-Te Yin.

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Shih, YW., Chien, ST., Chen, PS. et al. α-Mangostin Suppresses Phorbol 12-myristate 13-acetate-Induced MMP-2/MMP-9 Expressions via αvβ3 Integrin/FAK/ERK and NF-κB Signaling Pathway in Human Lung Adenocarcinoma A549 Cells. Cell Biochem Biophys 58, 31–44 (2010). https://doi.org/10.1007/s12013-010-9091-2

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Keywords

  • α-Mangostin
  • PMA
  • Invasion
  • Migration
  • αvβ3 Integrin
  • FAK
  • ERK1/2
  • MMP-2
  • MMP-9