생명과학회지 (Journal of Life Science)

  • 제22권5호
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  • Pages.697-701
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  • 2012
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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종양세포의 사멸에 있어서의 activated protein C의 효과

Effect of Activated Protein C (APC) on Apoptosis of Cancer Cells

  • 민경진 (계명대학교 의과대학 면역학교실) ;
  • 배종섭 (경북대학교 약학대학 약학연구소) ;
  • 권택규 (계명대학교 의과대학 면역학교실)
  • Min, Kyoung-Jin (Department of immunology, School of Medicine, Keimyung University) ;
  • Bae, Jong-Sup (College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Kwon, Taeg-Kyu (Department of immunology, School of Medicine, Keimyung University)
  • 투고 : 2012.03.12
  • 심사 : 2012.03.27
  • 발행 : 2012.05.30
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초록

본 연구에서는 항응고제로서의 역할을 가지면서 또한 혈액응고와는 관련 없는 종양세포의 전이 등을 조절하는 것으로 알려진 activated protein C (APC)가 종양세포의 사멸에는 어떠한 영향을 미치는 지에 대한 연구를 수행하였다. Tumor necrosis factor (TNF)-${\alpha}$와 cyclohexamide를 병합 처리하거나 FAS를 처리하게 되면 인간 신장암세포인 Caki에서는 유의적인 세포사멸이 일어난다. 하지만, APC는 이러한 세포사멸에 아무런 영향을 미치지 못하였다. 또한 TRAIL을 인간 뇌 암세포인 T98G와 유방암세포인 MDA231세포에 처리하여 세포사멸을 일으켰을 때에도 APC는 세포사멸을 조절하지 못하였다. 그러나, TRAIL에 대한 민감도를 증가시키기 위한 kahweol과 TRAIL의 병합처리나, kahweol과 malatonin의 병합처리에 의한 신장암세포의 사멸은 APC에 의해 유의적으로 억제되는 것을 확인하였다. 따라서, 이는 APC가 항암치료의 효율성을 조절 할 수 있는 가능성을 가짐을 의미한다.

Activated protein C (APC) has an anticoagulant effect and a non-hemostatic effect such as regulation of cell metastasis and modulation of inflammation. In this study, we investigated whether APC could modulate apoptosis in cancer cells. Tumor necrosis factor (TNF)-${\alpha}$, cyclohexamide, and FAS markedly induced apoptosis in human renal carcinoma Caki cells. When Caki cells were pretreated with APC, the percentage of death receptor-induced apoptosis did not change. Furthermore, we checked the effect of APC on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human glioma T98G and human breast carcinoma MDA231 cells. APC also had no effect on TRAIL-induced apoptosis in both cell lines. However, pretreatment with APC inhibited combination treatment (kahweol plus TRAIL and kahweol plus melatonin)-induced apoptosis and PARP cleavage in Caki cells. Taken together, our results suggest that APC can modulate anti-cancer therapeutic efficiency.

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참고문헌

  1. Altinbas, M., Coskun, H. S., Er, O., Ozkan, M., Eser, B., Unal, A., Cetin, M. and Soyuer, S. 2004. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J. Thromb. Haemost. 2, 1266-1271. https://doi.org/10.1111/j.1538-7836.2004.00871.x
  2. Beaulieu, L. M. and Church, F. C. 2007. Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1. Exp. Cell Res. 313, 677-687. https://doi.org/10.1016/j.yexcr.2006.11.019
  3. Bezuhly, M., Cullen, R., Esmon, C. T., Morris, S. F., West, K. A., Johnston, B. and Liwski, R. S. 2009. Role of activated protein C and its receptor in inhibition of tumor metastasis. Blood 113, 3371-3374. https://doi.org/10.1182/blood-2008-05-159434
  4. Cheng, T., Liu, D., Griffin, J. H., Fernández, J. A., Castellino, F., Rosen, E. D., Fukudome, K. and Zlokovic, B. V. 2003. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat. Med. 9, 338-342. https://doi.org/10.1038/nm826
  5. Chew, H. K., Wun, T., Harvey, D., Zhou, H. and White, R. H. 2006. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch. Intern. Med. 166, 458-464. https://doi.org/10.1001/archinte.166.4.458
  6. Donati, M. B. 2009. Thrombosis and cancer: Trousseau syndrome revisited. Best Pract. Res. Clin. Haematol. 22, 3-8. https://doi.org/10.1016/j.beha.2009.01.005
  7. Esmon, C. T., Vigano-D'Angelo, S., D'Angelo, A. and Comp, P. C. 1987. Anticoagulation proteins C and S. Adv. Exp Med. Biol. 214, 47-54.
  8. Esmon, N. L., Owen, W. G. and Esmon, C. T. 1982. Isolation of a membrane-bound cofactor for thrombin-catalyzed activation of protein C. J. Biol. Chem. 257, 859-864.
  9. Falschlehner, C., Emmerich, C. H., Gerlach, B. and Walczak, H. 2007. TRAIL signalling: decisions between life and death. Int. J. Biochem. Cell Biol. 39, 1462-1475. https://doi.org/10.1016/j.biocel.2007.02.007
  10. Klerk, C. P., Smorenburg, S. M., Otten, H. M., Lensing, A. W., Prins, M. H., Piovella, F., Prandoni, P., Bos, M. M., Richel, D. J., van Tienhoven, G. and Buller, H. R. 2005. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J. Clin. Oncol. 23, 2130-2135. https://doi.org/10.1200/JCO.2005.03.134
  11. Kobayashi, H., Moniwa, N., Gotoh, J., Sugimura, M. and Terao, T. 1994. Role of activated protein C in facilitating basement membrane invasion by tumor cells. Cancer Res. 54, 261-267.
  12. Nagata, S. 1994. Apoptosis regulated by a death factor and its receptor: Fas ligand and Fas. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 345, 281-287. https://doi.org/10.1098/rstb.1994.0107
  13. O'Brien, L. A., Richardson, M. A., Mehrbod, S. F., Berg, D. T., Gerlitz, B., Gupta, A. and Grinnell, B. W. 2007. Activated protein C decreases tumor necrosis factor related apoptosis-inducing ligand by an EPCR- independent mechanism involving Egr-1/Erk-1/2 activation. Arterioscler. Thromb. Vasc. Biol. 27, 2634-2641 https://doi.org/10.1161/ATVBAHA.107.153734
  14. Pajak, B., Gajkowska, B. and Orzechowski, A. 2005. Cycloheximide-mediated sensitization to TNF-alpha-induced apoptosis in human colorectal cancer cell line COLO 205; role of FLIP and metabolic inhibitors. J. Physiol. Pharmacol. 56, 101-118.
  15. Um, H. J., Oh, J. H., Kim, Y. N., Choi, Y. H., Kim, S. H., Park, J. W. and Kwon, T. K. 2010. The coffee diterpene kahweol sensitizes TRAIL-induced apoptosis in renal carcinoma Caki cells through down-regulation of Bcl-2 and c-FLIP. Chem. Biol. Interact. 186, 36-42. https://doi.org/10.1016/j.cbi.2010.04.013
  16. Um, H. J., Park, J. W. and Kwon, T. K. 2011. Melatonin sensitizes Caki renal cancer cells to kahweol-induced apoptosis through CHOP-mediated up-regulation of PUMA. J. Pineal Res. 50, 359-366. https://doi.org/10.1111/j.1600-079X.2010.00851.x
  17. Varki, A. 2007. Trousseau's syndrome: multiple definitions and multiple mechanisms. Blood 110, 1723-1729. https://doi.org/10.1182/blood-2006-10-053736
  18. Xue, M, Thompson, P., Kelso, I. and Jackson, C. 2004. Activated protein C stimulates proliferation, migration and wound closure, inhibits apoptosis and upregulates MMP-2 activity in cultured human keratinocytes. Exp. Cell Res. 299, 119-127. https://doi.org/10.1016/j.yexcr.2004.05.015