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인간 신장암 Caki세포에서 Par-4에 의한 MMP-2 활성 저해를 통한 세포 이동 조절

우선민;권택규
Woo, Seon Min;Kwon, Taeg Kyu

  • 투고 : 2016.04.22
  • 심사 : 2016.05.16
  • 발행 : 2016.05.30

초록

Par-4는 다양한 세포사멸 자극에 세포 사멸을 조절하고, 종양 억제기능을 가지고 있다. 그러나, Par-4에 의한 암세포의 이동 및 침윤에 대한 연구는 수행되지 않았다. 본 연구에서 Par-4단백질의 과발현이 인간 신장암 Caki세포에서 MMP-2의 활성화를 억제하지만 MMP-9 활성에는 영향을 주지 않았다. Par-4에 의한 MMP-2의 활성 억제는 leucine zipper domain이 결실된 Par-4 에서는 확인되지 않았다. Par-4 siRNA를 이용한 knock-down 실험에서 PMA 처리 시 세포이동 및 침윤 증가함을 확인하였다. Par-4의 과발현과 knock-dwon에서 MMP-2 mRNA 발현의 변화를 확인 할 수 없었다. 이 점은 Par-4 매개의 MMP-2 활성 억제는 전사 후 조절을 통하여 야기됨을 추측 할 수 있다.

키워드

Caki cells;cell migration;cell invasion;Matrix metalloproteinase-2;Par-4

참고문헌

  1. Cheema, S. K., Mishra, S. K., Rangnekar, V. M., Tari, A. M., Kumar, R. and Lopez-Berestein, G. 2003. Par-4 transcriptionally regulates Bcl-2 through a WT1-binding site on the bcl-2 promoter. J. Biol. Chem. 278, 19995-20005. https://doi.org/10.1074/jbc.M205865200
  2. Diaz-Meco, M. T., Municio, M. M., Frutos, S., Sanchez, P., Lozano, J., Sanz, L. and Moscat, J. 1996. The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C. Cell 86, 777-786. https://doi.org/10.1016/S0092-8674(00)80152-X
  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. Goswami, A., Burikhanov, R., de Thonel, A., Fujita, N., Goswami, M., Zhao, Y., Eriksson, J. E., Tsuruo, T. and Rangnekar, V. M. 2005. Binding and phosphorylation of par-4 by akt is essential for cancer cell survival. Mol Cell. 20, 33-44. https://doi.org/10.1016/j.molcel.2005.08.016
  5. Gurumurthy, S., Goswami, A., Vasudevan, K. M. and Rangnekar, V. M. 2005. Phosphorylation of Par-4 by protein kinase A is critical for apoptosis. Mol. Cell. Biol. 25, 1146-1161. https://doi.org/10.1128/MCB.25.3.1146-1161.2005
  6. Hebbar, N., Wang, C. and Rangnekar, V. M. 2012. Mechanisms of apoptosis by the tumor suppressor Par-4. J. Cell. Physiol. 227, 3715-3721. https://doi.org/10.1002/jcp.24098
  7. Irby, R. B. and Kline, C. L. 2013. Par-4 as a potential target for cancer therapy. Expert. Opin. Ther. Targets 17, 77-87. https://doi.org/10.1517/14728222.2013.731047
  8. Johnstone, R. W., See, R. H., Sells, S. F., Wang, J., Muthukkumar, S., Englert, C., Haber, D. A., Licht, J. D., Sugrue, S. P., Roberts, T., Rangnekar, V. M. and Shi, Y. 1996. A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms′ tumor suppressor WT1. Mol. Cell. Biol. 16, 6945-6956. https://doi.org/10.1128/MCB.16.12.6945
  9. Kato, Y., Yamashita, T. and Ishikawa, M. 2002. Relationship between expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 and invasion ability of cervical cancer cells. Oncol. Rep. 9, 565-569.
  10. Kogel, D., Plottner, O., Landsberg, G., Christian, S. and Scheidtmann, K. H. 1998. Cloning and characterization of Dlk, a novel serine/threonine kinase that is tightly associated with chromatin and phosphorylates core histones. Oncogene 17, 2645-2654. https://doi.org/10.1038/sj.onc.1202204
  11. Lambert, E., Dasse, E., Haye, B. and Petitfrere, E. 2004. TIMPs as multifacial proteins. Crit. Rev. Oncol. Hematol. 49, 187-198. https://doi.org/10.1016/j.critrevonc.2003.09.008
  12. Rah, B., Amin, H., Yousuf, K., Khan, S., Jamwal, G., Mukherjee, D. and Goswami, A. 2012. A novel MMP-2 inhibitor 3-azidowithaferin A (3-azidoWA) abrogates cancer cell invasion and angiogenesis by modulating extracellular Par-4. PLoS One 7, e44039.
  13. 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
  14. Soreide, K., Janssen, E. A., Korner, H. and Baak, J. P. 2006. Trypsin in colorectal cancer: molecular biological mechanisms of proliferation, invasion, and metastasis. J. Pathol. 209, 147-156. https://doi.org/10.1002/path.1999
  15. Uzui, H., Harpf, A., Liu, M., Doherty, T. M., Shukla, A. and Chai, N. 2002. Increased expression of membrane type 3-matrix metalloproteinase in human atherosclerotic plaque: role of activated macrophages and inflammatory cytokines. Circulation 106, 3024-3030. https://doi.org/10.1161/01.CIR.0000041433.94868.12
  16. 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
  17. 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