생명과학회지 (Journal of Life Science)

  • 제21권1호
  • /
  • Pages.89-95
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  • 2011
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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HCT116 대장암 세포에서 Akt-p53 신호경로를 통한 커큐민과 EGCG의 apoptosis 효과

Apoptotic Effects of Curcumin and EGCG via Akt-p53 Signaling Pathway in HCT116 Colon Cancer Cells

  • 박송이 (한남대학교 생명나노과학대학 생명과학과) ;
  • 이솔화 (한남대학교 생명나노과학대학 생명과학과) ;
  • 박옥진 (한남대학교 생명나노과학대학 식품영양학과) ;
  • 김영민 (한남대학교 생명나노과학대학 생명과학과)
  • Park, Song-Yi (Department of Biological Sciences, College of Life Science and Nano Technology, Hannam University) ;
  • Lee, Sol-Hwa (Department of Biological Sciences, College of Life Science and Nano Technology, Hannam University) ;
  • Park, Ock-Jin (Department of Food and Nutrition, College of Life Science and Nano Technology, Hannam University) ;
  • Kim, Young-Min (Department of Biological Sciences, College of Life Science and Nano Technology, Hannam University)
  • 투고 : 2010.11.03
  • 심사 : 2010.12.03
  • 발행 : 2011.01.30
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초록

식품에서 추출한 파이토케미컬은 여러 암종에서 암세포의 증식억제와 apoptosis를 유도한다. 최근에 이러한 파이토케미컬의 세포 내 신호전달 기작에 관한 관심이 높아지고 있으며, 본 연구에서는 파이토케미컬의 일종인 커큐민과 EGCG를 HCT116 대장암세포에 처리함으로써 암세포의 증식억제와 apoptosis 유도 효과를 알아보고, 암세포의 증식에 관여하는 Akt의 활성과 종양 억제유전자인 p53의 신호경로를 규명하고자 하였다. 그 결과, 커큐민과 EGCG를 처리했을 때 HCT116 세포의 증식이 억제되었고, 암세포에서 apoptosis 효과가 나타남을 확인하였다. 동일한 조건에서 Western blotting을 실시했을 때 Akt의 활성은 감소하였으며 p53의 발현은 증가하였다. 또한 Akt의 저해제인 LY294002를 처리했을 때 암세포의 증식이 더욱 강하게 억제되었으며, p53의 발현은 더욱 강하게 증가하는 것으로 나타났다. 따라서 HCT116 세포에서 커큐민과 EGCG 처리에 의한 암세포의 증식 억제 및 apoptosis는 p53의 발현이 증가함에 따라 유도되며, 이러한 p53의 발현 증가는 Akt 신호경로를 저해함으로써 일어난다는 것을 확인하였다.

p53 is tumor suppressor gene that regulates apoptosis such as caspase-dependent and p21-mediated signaling pathways. PI3K/Akt is known to be over-activated in cancer cells. Akt activates many survival-related signals such as mTOR and COX-2. Inactivation of Akt would result in non-inhibition of p53 as well as induced apoptosis. In this study, we showed that curcumin and EGCG activate p53 via inhibition of the Akt signaling pathway. Treatments using curcumin and EGCG in different concentrations for 24 hr and 48 hr inhibited proliferation of HCT116 colon cancer cells and increased apoptotic cell death. Also, our data showed that curcumin and EGCG increased the p53 expression and decreased the p-Akt. Treatment of LY294002 (Akt inhibitor) resulted in decreased cell proliferation of cancer cells, while LY294002 treated with curcumin or EGCG showed a greater decrease of cell proliferation. In addition, inhibition of Akt induced p53 activation in HCT116 colon cancer cells. These results suggest that curcumin and EGCG induce apoptosis by inhibiting Akt and increase p53 in HCT116 colon cancer cells.

키워드

참고문헌

  1. Amaral, J. D., J. M. Xavier, C. J. Steer, and C. M. Rodrigues. 2010. The role of p53 in apoptosis. Discov. Med. 9, 145-152.
  2. Banerjee, M., P. Singh, and D. Panda. 2010. Curcumin suppresses the dynamic instability of microtubules, activates the mitotic checkpoint and induces apoptosis in MCF-7 cells. FEBS J. 277, 3437-3448. https://doi.org/10.1111/j.1742-4658.2010.07750.x
  3. Carnero, A. 2010. The PKB/AKT pathway in cancer. Curr. Pharm. Des. 16, 34-44. https://doi.org/10.2174/138161210789941865
  4. Gottlieb, T. M., J. F. Leal, R. Seger, Y. Taya, and M. Oren. 2002. Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 21, 1299-1303. https://doi.org/10.1038/sj.onc.1205181
  5. Inaba, H., Y. Nagaoka, Y. Kushima, A. Kumagai, Y. Matsumoto, M. Sakaguchi, K. Baba, and S. Uesato. 2008. Comparative examination of anti-proliferative activities of (-)-epigallocatechin gallate and (--)-epigallocatechin against HCT116 colorectal carcinoma cells. Biol. Pharm. Bull. 31, 79-84. https://doi.org/10.1248/bpb.31.79
  6. Jemal, A., R. Siegel, J. Xu, and E. Ward. 2010. Cancer statistics, 2010. CA. Cancer J. Clin. 60, 277-300. https://doi.org/10.3322/caac.20073
  7. Lee, Y. K., S. Y. Park, Y. M. Kim, and O. J. Park. 2009. Regulatory effect of the AMPK-COX-2 signaling pathway in curcumin-induced apoptosis in HT-29 colon cancer cells. Ann. N. Y. Acad. Sci. 1171, 489-494. https://doi.org/10.1111/j.1749-6632.2009.04699.x
  8. Lee, Y. K., S. Y. Park, Y. M. Kim, D. C. Kim, W. S. Lee, Y. J. Surh, and O. J. Park. 2010. Suppression of mTOR via Akt-dependent and -independent mechanisms in selenium- treated colon cancer cells: involvement of AMPKalpha1. Carcinogenesis 31, 1092-1099. https://doi.org/10.1093/carcin/bgq040
  9. Lee, Y. K., W. S. Lee, J. T. Hwang, D. Y. Kwon, Y. J. Surh, and O. J. Park. 2009. Curcumin exerts antidifferentiation effect through AMPKalpha-PPAR-gamma in 3T3-L1 adipocytes and antiproliferatory effect through AMPKalpha- COX-2 in cancer cells. J. Agric. Food Chem. 57, 305-310. https://doi.org/10.1021/jf802737z
  10. Milacic, V., S. Banerjee, K. R. Landis-Piwowar, F. H. Sarkar, A. P. Majumdar, and Q. P. Dou. 2008. Curcumin inhibits the proteasome activity in human colon cancer cells in vitro and in vivo. Cancer Res. 68, 7283-7292. https://doi.org/10.1158/0008-5472.CAN-07-6246
  11. Okoshi, R., T. Ozaki, H. Yamamoto, K. Ando, N. Koida, S. Ono, T. Koda, T. Kamijo, A. Nakagawara, and H. Kizaki. 2008. Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress. J. Biol. Chem. 283, 3979-3987. https://doi.org/10.1074/jbc.M705232200
  12. Osaki, M., M. Oshimura, and H. Ito. 2004. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis 9, 667-676. https://doi.org/10.1023/B:APPT.0000045801.15585.dd
  13. Park, I. J., Y. K. Lee, J. T. Hwang, D. Y. Kwon, J. Ha, and O. J. Park. 2009. Green tea catechin controls apoptosis in colon cancer cells by attenuation of H2O2-stimulated COX-2 expression via the AMPK signaling pathway at low-dose $H_2O_2$. Ann. N. Y. Acad. Sci. 1171, 538-544. https://doi.org/10.1111/j.1749-6632.2009.04698.x
  14. Rao, S. D., and K. Pagidas. 2010. Epigallocatechin-3-gallate, a natural polyphenol, inhibits cell proliferation and induces apoptosis in human ovarian cancer cells. Anticancer Res. 30, 2519-2523.
  15. Sarkar, F. H. and Y. Li. 2004. Cell signaling pathways altered by natural chemopreventive agents. Mutat. Res. 555, 53-64. https://doi.org/10.1016/j.mrfmmm.2004.04.015
  16. Seitz, S. J., E. S. Schleithoff, A. Koch, A. Schuster, A. Teufel, F. Staib, W. Stremmel, G. Melino, P. H. Krammer, T. Schilling, and M. Muller. 2010. Chemotherapy-induced apoptosis in hepatocellular carcinoma involves the p53 family and is mediated via the extrinsic and the intrinsic pathway. Int. J. Cancer 126, 2049-2066.
  17. Sheu, M. J., P. Y. Chou, C. S. Huang, I. C. Tsai, Y. C. Chien, S. Y. Lin, H. Y. Tsai, H. C. Cheng, and C. H. Wu. 2010. Pipoxolan inhibits proliferation of HL-60 human leukaemia cancer cells by arresting the cell cycle at the G0/G1 phase. Clin. Exp. Pharmacol. Physiol. 37, 605-612. https://doi.org/10.1111/j.1440-1681.2010.05358.x
  18. Tachibana, H. 2009. Molecular basis for cancer chemoprevention by green tea polyphenol EGCG. Forum. Nutr. 61, 156-169. https://doi.org/10.1159/000212748
  19. Watson, J. L., R. Hill, P. W. Lee, C. A. Giacomantonio, and D. W. Hoskin. 2008. Curcumin induces apoptosis in HCT-116 human colon cancer cells in a p21-independent manner. Exp. Mol. Pathol. 84, 230-233. https://doi.org/10.1016/j.yexmp.2008.02.002
  20. Wu, A. H., R. G. Ziegler, P. L. Horn-Ross, A. M. Nomura, D. W. West, L. N. Kolonel, J. F. Rosenthal, R. N. Hoover, and M. C. Pike. 1996. Tofu and risk of breast cancer in Asian-Americans. Cancer Epidemiol. Biomarkers Prev. 5, 901-906.
  21. Wu, P. P., S. C. Kuo, W. W Huang, J. S. Yang, K. C. Lai, H. J. Chen, K. L. Lin, Y. J. Chiu, L. J. Huang, and J. G Chung. 2009. (-)-Epigallocatechin gallate induced apoptosis in human adrenal cancer NCI-H295 cells through caspase-dependent and caspase-independent pathway. Anticancer Res. 29, 1435-1442.
  22. Wu, S. H., L. W. Hang, J. S. Yang, H. Y. Chen, H. Y. Lin, J. H. Chiang, C. C. Lu, J. L. Yang, T. Y. Lai, Y. C. Ko, and J. G. Chung. 2010. Curcumin induces apoptosis in human non-small cell lung cancer NCI-H460 cells through ER stress and caspase cascade- and mitochondria-dependent pathways. Anticancer Res. 30, 2125-2133.
  23. Xing, C. G., B. S. Zhu, H. H. Liu, F. Lin, H. H. Yao, Z. Q. Liang, and Z. H. Qin. 2008. LY294002 induces p53-dependent apoptosis of SGC7901 gastric cancer cells. Acta. Pharmacol. Sin. 29, 489-498. https://doi.org/10.1111/j.1745-7254.2008.00770.x
  24. Yoeli-Lerner, M., G. K. Yiu, I. Rabinovitz, P. Erhardt, S. Jauliac, and A. Toker. 2005. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol. Cell 20, 539-550. https://doi.org/10.1016/j.molcel.2005.10.033

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