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.
Similar content being viewed by others
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
Greenlee, R. T., Hill-Harmon, M. B., Murraym, T., & Thunm, M. (2001). Cancer statistics. CA: A Cancer Journal for Clinicians, 51, 15–36.
Gupta, G. P., & Massague, J. (2006). Cancer metastasis: building a framework. Cell, 127, 679–695.
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.
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.
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.
Peres, V., & Nagem, T. J. (1997). Trioxygenated naturally occurring xanthones. Phytochemistry, 44, 191–214.
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.
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.
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.
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.
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.
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.
Woodhouse, E. C., Chuaqui, R. F., & Liotta, L. A. (1997). General mechanisms of metastasis. Cancer, 180, 1529–1537.
Humphries, M. J. (2000). Integrin structure. Biochemical Society Transactions, 28, 311–339.
Stupack, D. G. (2007). The biology of integrins. Oncology, 21, 6–12.
van Nimwegen, M. J., & van de Water, B. (2007). Focal adhesion kinase: A potential target in cancer therapy. Biochemical Pharmacology, 73, 597–609.
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.
Lauffenburger, D. A., & Horwitz, A. F. (1996). Cell migration: A physically integrated molecular process. Cell, 84, 359–369.
Siesser, P. M., & Hanks, S. K. (2006). The signaling and biological implications of FAK over-expression in cancer. Clinical Cancer Research, 12, 3233–3237.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
El-Tanani, M. K. (2008). Role of osteopontin in cellular signaling and metastatic phenotype. Frontiers in Bioscience, 13, 4276–4284.
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.
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.
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.
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.
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.
Carpenter, C. L., & Cantley, L. C. (1996). Phosphoinositide kinases. Current Opinion in Cell Biology, 8, 153–158.
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.
Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65, 55–63.
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.
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.
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.
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.
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.
Bharti, A. C., & Aggarwal, B. B. (2002). Nuclear factor-kappa B and cancer: Its role in prevention and therapy. Biochemical Pharmacology, 64, 883–888.
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.
Sundaram, B. M., Gopalakrishnan, C., Subramanian, S., Shankaranarayanan, D., & Kameswaran, L. (1983). Antimicrobial activities of Garcinia mangostana. Planta Medica, 48, 59–60.
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.
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.
Miranti, C. K., & Bruggem, J. S. (2002). Sensing the environment: A historical perspective on integrin signal transduction. Nature Cell Biology, 4, E83–E90.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12013-010-9091-2