생명과학회지 (Journal of Life Science)

  • 제23권3호
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  • Pages.355-360
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  • 2013
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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인간 자궁경부암세포인 Caski세포에서 withaferin A에 의한 PMA 매개 matrix metalloproteinase-9의 발현 억제 효과

Withaferin A Inhibits PMA-Induced MMP-9 Expression in Human Cervical Carcinoma Caski Cells

  • 김동은 (계명대학교 의과대학 이비인후과)
  • Kim, Dong Eun (Department of Otolaryngology, School of Medicine, Keimyung University)
  • 투고 : 2013.03.04
  • 심사 : 2013.03.26
  • 발행 : 2013.03.30
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초록

Withaferin A는 Withania somnifera라는 식물에서 추출한 스테로이드 락톤으로 항염증, 항암, 그리고 면역중재 작용과 같은 다양한 역할을 한다. 그러나, withaferin A에 의한 MMP-9의 발현 및 활성화 조절에 대한 연구는 수행되지 않았다. 본 연구에서 우리는 withaferin A가 인간 자궁경부암세포인 Caski세포에서 PMA 매개의 MMP-9의 발현과 활성화를 조절 할 수 있는지 확인하였다. Withaferin A는 농도의존적으로 PMA유도 MMP-9의 활성을 억제하였고, MMP-9의 promoter assay를 통하여 전사단계에서 조절됨을 확인하였다. 또한, Withaferin A 의한 PMA 유도 MMP-9의 mRNA와 단백질 발현이 억제됨을 확인하였다. 이러한, withaferin A에 의한 MMP-9 발현 조절 전사인자로는 NF-${\kappa}B$가 관여함을 확인하였다. Withaferin A는 PMA에 의한 세포이동을 억제하였는데, 이러한 현상은 MMP-9의 발현 및 활성을 조절함으로써 일어날 수 있음을 확인하였다.

Withaferin A is an active component of Withania somnifera, and has anti-inflammatory, anti-tumor, and immune modulatory effects. However, the effects of withaferin A on metalloproteinase (MMP)-9 expression and activity have not been investigated. In this study, we investigated the ability of withaferin A to inhibit MMP-9 expression and activity in PMA-treated human cervical carcinoma Caski cells. Withaferin A markedly inhibited the PMA-induced MMP-9 activity in a dose-dependent manner. Withaferin A decreased not only PMA-induced MMP-9 promoter activity but also PMA-mediated MMP-9 mRNA and protein expression in Caski cells. NF-${\kappa}B$ promoter activity, which is important in MMP-9 expression, was also decreased in combined treatment with withaferin A and PMA. Furthermore, withaferin A markedly suppressed the ability of PMA-mediated migration in Caski cells. Our findings suggest that withaferin A might inhibit PMA-induced migration through the down-regulation of MMP-9 expression and activity.

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참고문헌

  1. Amalinei, C., Caruntu, I. D. and Balan, R. A. 2007. Biology of metalloproteinases. Rom J Morphol Embryol 48, 323-334.
  2. Farabegoli, F., Papi, A. and Orlandi, M. 2011. (-)-Epigallocatechin-3-gallate down-regulates EGFR, MMP-2, MMP-9 and EMMPRIN and inhibits the invasion of MCF-7 tamoxifen-resistant cells. Biosci Rep 31, 99-108. https://doi.org/10.1042/BSR20090143
  3. Festuccia, C., Giunciuglio, D., Guerra, F., Villanova, I., Angelucci, A., Manduca, P., Teti, A., Albini, A. and Bologna, M. 1999. Osteoblasts modulate secretion of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) in human prostate cancer cells promoting migration and matrigel invasion. Oncol Res 11, 17-31.
  4. Hah, N. and Lee, S. T. 2003. An absolute role of the PKC-dependent NF-kappaB activation for induction of MMP-9 in hepatocellular carcinoma cells. Biochem Biophys Res Commun 305, 428-433. https://doi.org/10.1016/S0006-291X(03)00788-5
  5. Hung, W. C., Tseng, W. L., Shiea, J. and Chang, H. C. 2010. Skp2 overexpression increases the expression of MMP-2 and MMP-9 and invasion of lung cancer cells. Cancer Lett 288, 156-161. https://doi.org/10.1016/j.canlet.2009.06.032
  6. Koduru, S., Kumar, R., Srinivasan, S., Evers, M. B. and Damodaran, C. 2010. Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis. Mol Cancer Ther 9, 202-210.
  7. Kumar, B., Koul, S., Petersen, J., Khandrika, L., Hwa, J. S., Meacham, R. B., Wilson, S. and Koul, H. K. 2010. p38 mitogen- activated protein kinase-driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity. Cancer Res 70, 832-841. https://doi.org/10.1158/0008-5472.CAN-09-2918
  8. Lee, E. J., Kim, S. Y., Hyun, J. W., Min, S. W., Kim, D. H. and Kim, H. S. 2010. Glycitein inhibits glioma cell invasion through down-regulation of MMP-3 and MMP-9 gene expression. Chem Biol Interact 185, 18-24. https://doi.org/10.1016/j.cbi.2010.02.037
  9. Lee, T. J., Um, H. J., Min do, S., Park, J. W., Choi, K. S. and Kwon, T. K. 2009. Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP. Free Radic Biol Med 46, 1639-1649. https://doi.org/10.1016/j.freeradbiomed.2009.03.022
  10. Masson, V., de la Ballina, L. R., Munaut, C., Wielockx, B., Jost, M., Maillard, C., Blacher, S., Bajou, K., Itoh, T., Itohara, S., Werb, Z., Libert, C., Foidart, J. M. and Noel, A. 2005. Contribution of host MMP-2 and MMP-9 to promote tumor vascularization and invasion of malignant keratinocytes. FASEB J 19, 234-236.
  11. Mohan, R., Hammers, H. J., Bargagna-Mohan, P., Zhan, X. H., Herbstritt, C. J., Ruiz, A., Zhang, L., Hanson, A. D., Conner, B. P., Rougas, J. and Pribluda, V. S. 2004. Withaferin A is a potent inhibitor of angiogenesis. Angiogenesis 7, 115-122. https://doi.org/10.1007/s10456-004-1026-3
  12. Nalla, A. K., Gorantla, B., Gondi, C. S., Lakka, S. S. and Rao, J. S. 2010. Targeting MMP-9, uPAR, and cathepsin B inhibits invasion, migration and activates apoptosis in prostate cancer cells. Cancer Gene Ther 17, 599-613. https://doi.org/10.1038/cgt.2010.16
  13. Ndlovu, M. N., Van Lint, C., Van Wesemael, K., Callebert, P., Chalbos, D., Haegeman, G. and Vanden Berghe, W. 2009. Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells. Mol Cell Biol 29, 5488-5504. https://doi.org/10.1128/MCB.01657-08
  14. Oh, J. H., Lee, T. J., Kim, S. H., Choi, Y. H., Lee, S. H., Lee, J. M., Kim, Y. H., Park, J. W. and Kwon, T. K. 2008. Induction of apoptosis by withaferin A in human leukemia U937 cells through down-regulation of Akt phosphorylation. Apoptosis 13, 1494-1504. https://doi.org/10.1007/s10495-008-0273-y
  15. Park, M. J., Park, I. C., Lee, H. C., Woo, S. H., Lee, J. Y., Hong, Y. J., Rhee, C. H., Lee, Y. S., Lee, S. H., Shim, B. S., Kuroki, T. and Hong, S. I. 2003. Protein kinase C-alpha activation by phorbol ester induces secretion of gelatinase B/MMP-9 through ERK 1/2 pathway in capillary endothelial cells. Int J Oncol 22, 137-143.
  16. Ramos-DeSimone, N., Hahn-Dantona, E., Sipley, J., Nagase, H., French, D. L. and Quigley, J. P. 1999. Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/ stromelysin-1 cascade enhances tumor cell invasion. J Biol Chem 274, 13066-13076. https://doi.org/10.1074/jbc.274.19.13066
  17. Shin, M., Yan, C. and Boyd, D. 2002. An inhibitor of c-jun aminoterminal kinase (SP600125) represses c-Jun activation, DNA-binding and PMA-inducible 92-kDa type IV collagenase expression. Biochim Biophys Acta 1589, 311-316. https://doi.org/10.1016/S0167-4889(02)00195-7
  18. Sil, H., Sen, T. and Chatterjee, A. 2011. Fibronectin-integrin (alpha5beta1) modulates migration and invasion of murine melanoma cell line B16F10 by involving MMP-9. Oncol Res 19, 335-348. https://doi.org/10.3727/096504011X13079697132925
  19. Singh, D., Aggarwal, A., Maurya, R. and Naik, S. 2007. Withania somnifera inhibits NF-kappaB and AP-1 transcription factors in human peripheral blood and synovial fluid mononuclear cells. Phytother Res 21, 905-913. https://doi.org/10.1002/ptr.2180
  20. Thaiparambil, J. T., Bender, L., Ganesh, T., Kline, E., Patel, P., Liu, Y., Tighiouart, M., Vertino, P. M., Harvey, R. D., Garcia, A. and Marcus, A. I. 2011. Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation. Int J Cancer 129, 2744-2755. https://doi.org/10.1002/ijc.25938
  21. Um, H. J., Min, K. J., Kim, D. E. and Kwon, T. K. 2012. Withaferin A inhibits JAK/STAT3 signaling and induces apoptosis of human renal carcinoma Caki cells. Biochem Biophys Res Commun 427, 24-29. https://doi.org/10.1016/j.bbrc.2012.08.133
  22. Visse, R. and Nagase, H. 2003. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92, 827-839. https://doi.org/10.1161/01.RES.0000070112.80711.3D
  23. Woo, J. H., Lim, J. H., Kim, Y. H., Suh, S. I., Min, D. S., Chang, J. S., Lee, Y. H., Park, J. W. and Kwon, T. K. 2004. Resveratrol inhibits phorbol myristate acetate-induced matrix metalloproteinase-9 expression by inhibiting JNK and PKC delta signal transduction. Oncogene 23, 1845-1853. https://doi.org/10.1038/sj.onc.1207307
  24. Yang, E. S., Choi, M. J., Kim, J. H., Choi, K. S. and Kwon, T. K. 2011. Withaferin A enhances radiation-induced apoptosis in Caki cells through induction of reactive oxygen species, Bcl-2 downregulation and Akt inhibition. Chem Biol Interact 190, 9-15. https://doi.org/10.1016/j.cbi.2011.01.015