본문 바로가기
HOME> 논문 > 논문 검색상세

논문 상세정보

생명과학회지 = Journal of life science v.18 no.1 = no.93, 2008년, pp.120 - 128   피인용횟수: 6

지금초 추출물에 의한 TRAIL 저항성 인체위암세포의 세포사멸 유도
Euphorbiae Immifusae Sensitizes Apoptosis of TRAIL-resistant Human Gastric Adenocarcinoma AGS Cells

이재준   (동의대학교 한의과대학 내과학교실UU0000509  ); 신동역   (동의대학교 생화학교실 및 대학원 바이오물질제어학과UU0000509  ); 박상은   (동의대학교 한의과대학 내과학교실UU0000509  ); 김원일   (동의대학교 한의과대학 내과학교실UU0000509  ); 박동일   (동의대학교 한의과대학 내과학교실UU0000509  ); 최영현   (동의대학교 생화학교실 및 대학원 바이오물질제어학과UU0000509  ); 홍상훈   (동의대학교 한의과대학 내과학교실UU0000509  );
  • 초록

    본 연구에서는 지금초 열수 추출물(WEEH)의 처리에 의한 TRAIL 저항성 인체 위암세포의 증식 억제와 연관된 apoptosis유발에 관한 기전 해석을 시도하였다. 이를 위하여 AGS 세포주가 사용되었으며 다음과 같은 결과를 얻었다. 본 연구에서 조사된 범위 내에서의 TRAIL (200 ng/ml) 및 WEEH (0.04 mg/ml)의 단독 처리에 의한 AGS 세포에 유의적인 세포 독성을 나타내지 않았다. 그러나 TRAIL 및 WEEH의 혼합 처리는 WEEH의 처리 농도의존적으로 AGS 세포의 증식을 억제하였으며, 이는 apoptosis 유발에 의한 것임을 MTT assay, 핵의 염색질 응축 및 세포주기 sub-G1기에 속하는 세포빈도의 증가 등으로 확인하였다. TRAIL 및 WEEH 혼합 처리에 의한 apoptosis 유발 기전의 해석을 위하여 다양한 생화학적 분석법에 의하여 조사된 결과에 의하면, TRAIL 및 WEEH 혼합처리에 의한 caspase-8의 활성화에 의한 BID의 truncation화 및 이와 연관된 미토콘드리아 기능의 손상에 따른 caspase-9의 활성화와 연관성이 있었다. 이러한 미토콘드리아 기능 손상 및 caspase-9의 활성화는 Bcl-2, Bcl-xL, XIAP 및 cIAP-2등과 같은 anti-apoptotic 인자들의 발현 저하와 연관성이 있는 것이며, 이로 인한 caspase-3의 활성화에 의한 PARP 단백질의 단편화 유도로 apoptosis가 일어난 것으로 예측되어 진다. 비록 부가적인 연구들이 요구되어지지만, 본 연구의 결과는 TRAIL저항성 암세포의 항암전략에 지금초 추출물의 적용 가능성을 보여주는 것으로서 지금초의 항암작용의 규명에 중요한 자료를 제공하여 줄 것으로 생각된다.


    The death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/ Apo1L is a cytokine that activates apoptosis through cell surface death receptors. TRAIL has sparked growing interest in oncology due to its reported ability to selectively trigger cancer cell death. Euphorbiae humifusae Wind has been used in traditional Oriental medicine as a folk remedy used for the treatment of cancer. However, the mechanism responsible for the anticancer effects of E. humifusae not clearly understood. Here, we show that treatment with subtoxic doses of water extract of E. humifusae (WEEH) in combination with TRAIL induces apoptosis in TRAIL-resistant human gastric carcinoma AGS cells. Combined treatment with WEEH and TRAIL induced chromatin condensation and sub-G1 phase DNA content. These indicators of apoptosis were correlated with the induction of caspase activity that resulted in the cleavage of poly (ADP-ribose) polymerase. Combined treatment also triggered the loss of mitochondrial membrane potential. Furthermore, co-treatment with WEEH and TRAIL down-regulated the protein levels of the anti-apoptotic proteins such as Bcl-2, Bcl-xL, XIAP and cIAP-1. Although more study will be needed to examine the detailed mechanisms, this combined treatment may offer an attractive strategy for safely treating gastric adenocarcinomas and the results provide important new insights into the possible molecular mechanisms of the anticancer activity of E. humifusae.


  • 주제어

    Euphorbiae humifusae .   TNF-related apoptosis-inducing ligand(TRAIL) .   apoptosis .   mitochondrial membrane potential .   caspase.  

  • 참고문헌 (33)

    1. Holcik, M., H. Gibson and R. G. Korneluk. 2001. XIAP: apoptotic brake and promising therapeutic target. Apoptosis 6, 253-261. 
    2. Griffith, T. S. and D. H. Lynch. 1998. TRAIL: a molecule with multiple receptors and control mechanisms. Curr. Opin. Immunol. 10, 559-563. 
    3. Gerschenson, L. E. and R. J. Rotello. 1992. Apoptosis: a different type of cell death. FASEB J. 6, 2450-2455. 
    4. Jurgensmeier, J. M., Z. Xie, Q. Deveraux, L. Ellerby, D. Bredesen and J. C. Reed. 1998. Bax directly induces release of cytochrome c from isolated mitochondria. Proc. Natl. Acad. Sci. USA 95, 4997-5002. 
    5. Jung, E. M., J. H. Lim, T. J. Lee, J. W. Park, K. S. Choi and T. K. Kwon, 2005. Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5). Carcinogenesis 26, 1905-1913. 
    6. Hussein, M. R., A. K. Haemel and G. S. Wood. 2003. Apoptosis and melanoma: molecular mechanisms. J. Pathol. 199, 275-288. 
    7. Lazebnik, Y. A., S. H. Kaufmann, S. Desnoyers, G. G. Poirier and W. C. Earnshaw. 1994. Cleavage of poly (ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371, 346-347. 
    8. Kischkel, F. C., D. A. Lawrence, A Chuntharapai, P. Schow, K. J. Kim and A. Ashkenazi. 2000. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 12, 611-620. 
    9. Kelley, J. Rand J. M. Duggan. 2003. Gastric cancer epidemiology and risk factors. J. Clin. Epidemiol. 56, 1-9. 
    10. Kim, Y. H., J. W. Park, J. Y. Lee and T. K. Kwon, 2004. Sodium butyrate sensitizes TRAIL-mediated apoptosis by induction of transcription from the DR5 gene promoter through Sp1 sites in colon cancer cells. Carcinogenesis 25, 1813-1820. 
    11. Kaufmann, S. H., S. Desnoyers, Y. Ottaviano, N. E. Davidson and G. G. Poirier. 1993. Specific proteolytic cleavage of poly (ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis, Cancer Res. 53, 3976-3985. 
    12. Antonsson, B. and J. C. Martinou. 2000. The Bcl-2 protein family. Exp. Cell Res. 256, 50-57. 
    13. Anderson, D. M., E. Maraskovsky, W. L. Billingsley, W. C. Dougall, M. E. Tometsko, E. R. Roux, M. C. Teepe, R. F. DuBose, D. Cosman and L. Galibert. 1997. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175-179. 
    14. Barranco, S. C., C. M. Townsend, Jr. C. Casartelli, B .G. Macik, N. L. Burger, W.R. Boerwinkle and W. K. Gourley. 1983. Establishment and characterization of an in vitro model system for human adenocarcinoma of the stomach. Cancer Res. 43, 1703-1709. 
    15. Bodmer, J. L., K. Burns, P. Schneider, K. Hofmann, V. Steiner, M. Thome, T. Bornand, M. Hahne, M. Schroter, K. Becker, A. Wilson, L. E. French, J. L. Browning, H. R. MacDonald and J. Tschopp. 1997. TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas (Apo-1/CD95). Immunity 6, 79-88. 
    16. Choi J. G. 2006. The medicine of grasses flowers and trees 2, pp. 193-201, Hanmunwha, Seoul. 
    17. Chu, X. L., C. S. Fan and Y. Z. Luo. 1997. Identification of Euphorbia humifusa Wind, and E. maculata Raf. from its confused species E. thymifolia L. Zhongguo Zhong Yao Za Zhi 19, 325-357. 
    18. French, L. E. and J. Tschopp. 1999. The TRAIL to selective tumor death. Nat. Med. 5, 146-147. 
    19. Reed, J. C. 1998. Bcl-2 family proteins. Oncogene 17, 3225-3236. 
    20. Park, S. Y. and D. W. Seol. 2002. Regulation of Akt by EGF-R inhibitors, a possible mechanism of EGF-R inhibitor-enhanced TRAIL-induced apoptosis. Biochem. Biophys. Res. Commun. 295, 515-518. 
    21. Myong, Y.H. and Y.H. Choi. 2007. Gastric cancer; Epidemiology and causes. Cancer Prev. Res. 12, 143-153. 
    22. Nozawa, F., A. Itami, M. Saruc, M. Kim, J. Standop. K. S. Picha, K. H. Cowan and P. M. Pour. 2004. The combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) and genistein is effective in inhibiting pancreatic cancer growth. Pancreas 29, 45-52. 
    23. Miyashita, T. and J. C. Reed. 1995. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293-299. 
    24. Yoshida, T., Y. Amakura, Y. Z. Liu and T. Okuda. 1994. Tannins and related polyphenols of euphorbiaceous plants. XI. Three new hydrolyzable tannins and a polyphenol glucoside from Euphorbia humifusa. Chem. Pharm. Bull. (Tokyo) 42, 1803-1807. 
    25. Yang, L. Q., D. C. Fang, Q. R. Wang and S. M. Yang. 2004. Effect of NF-$\kappa$B, survivin, Bcl-2 and caspase-3 on apoptosis of gastric cancer cells induced by tumor necrosis factor related apoptosis inducing ligand. World J. Gastroenterol. 10, 22-25. 
    26. Zhang, X. D., A. Franco, K. Myers, C. Gray, T. Nguyen and P. Hersey. 1999. Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res. 59, 2747-2753. 
    27. Tewari, M., L. T. Quan, K. O'Rourke, S. Desnoyers, Z. Zeng, D. R. Beidler, G. G. Poirier, G. S. Salvesen and V. M. Dixit. 1995. Yama/CPP32 $\beta$, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly (ADP-ribose) polymerase. Cell 81, 801-809. 
    28. Walczak, H., R. E. Miller, K. Ariail, B. Gliniak, T. S. Griffith, M. Kubin, W. Chin, J. Jones, A. Woodward, T. Le, C. Smith, P. Smolak, P. G. Goodwin, C. T. Rauch, J. C. Schuh and D.H. Lynch. 1999. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat. Med. 5, 157-163. 
    29. Wang, S. and S. W. EI-Deiry. 2003. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 22, 8628-8633. 
    30. Jin, C. Y., C. Park, J. H. Cheong, B. T. Choi, T. H. Lee, J. D. Lee, W. H. Lee, G. Y. Kim, C. H. Ryu and Y. H. Choi, 2007. Genistein sensitizes TRAIL-resistant human gastric adenocarcinoma AGS cells through activation of caspase-3. Cancer Lett. 257, 56-64. 
    31. Rosse, T., R. Olivier, L. Monney, M. Rager, S. Conus, I. Fellay, B. Jansen and C. Borner. 1998. Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Nature 391, 496-499. 
    32. Schultz, D. R. and W. J. Harrington Jr. 2003. Apoptosis: programmed cell death at a molecular level. Semin. Arthritis Rheum. 32, 345-369. 
    33. Srivastava, R. K. 2001. TRAIL/ Apo-2L: mechanisms and clinical applications in cancer. Neoplasia 3, 535-546. 
  • 이 논문을 인용한 문헌 (6)

    1. Hwang, Sung-Yeoun ; Ahn, Seong-Hun ; Keum, Kyung-Sao 2009. "Proposal on Spplementation to Oriental Medical Policy for the Revitalization of Oriental Medical Therapy for Stomach Cancer" 동의생리병리학회지 = Journal of physiology & pathology in Korean Medicine, 23(3): 528~533     
    2. Jeong, Myoung-Hoon ; Kim, Seung-Seop ; Ha, Ji-Hye ; Jin, Ling ; Lee, Hak-Ju ; Kang, Ha-Young ; Park, Sung-Jin ; Lee, Hyeon-Yong 2009. "Enhancement of Anticancer Activity of Acer mono by High Pressure Extraction Process" 한국식품영양과학회지 = Journal of the Korean Society of Food Science and Nutrition, 38(9): 1243~1252     
    3. Ha, Ji-Hye ; Jeong, Hyang-Suk ; Jeong, Myoung-Hoon ; Kim, Seung-Seop ; Jin, Ling ; Nam, Jong-Hyun ; Hwang, Baik ; Ma, Choong-Je ; Lee, Hyeon-Yong 2009. "Comparison of Anticancer Activities of Ultrasonification Extracts of Callus and Roots from Rhodiola sachalinensis A. Bor" 한국식품과학회지 = Korean journal of food science and technology, 41(5): 552~559     
    4. Ha, Ji-Hye ; Jeong, Myeong-Hoon ; Seo, Yong-Chang ; Choi, Woon-Yong ; Jeong, Heon-Sang ; Jung, Jae-Hyun ; Yu, Kwang-Wan ; Lee, Hyeon-Yong 2010. "Enhancement of Anticancer Activities of Low Quality Ginseng by Phelinus linteus Fermentation" 韓國藥用作物學會誌 = Korean journal of medicinal crop science, 18(3): 135~142     
    5. Park, Myoung-Su ; Jeong, Bo-Reum ; Bahk, Gyung-Jin 2015. "Antioxidant Activity and Cytotoxicity of Ethanol Extracts from Different Parts of Taraxacum coreanum Nakai cultivated in South Korea" 한국식품영양학회지 = The Korean journal of food and nutrition, 28(4): 594~601     
    6. Park, Myoung-Su ; So, Ji-Sun ; Bahk, Gyung-Jin 2015. "Antioxidative and Anticancer Activities of Water Extracts from Different Parts of Taraxacum coreanum Nakai Cultivated in Korea" 한국식품영양과학회지 = Journal of the Korean Society of Food Science and Nutrition, 44(8): 1234~1240     

 활용도 분석

  • 상세보기

    amChart 영역
  • 원문보기

    amChart 영역

원문보기

무료다운로드
유료다운로드

유료 다운로드의 경우 해당 사이트의 정책에 따라 신규 회원가입, 로그인, 유료 구매 등이 필요할 수 있습니다. 해당 사이트에서 발생하는 귀하의 모든 정보활동은 NDSL의 서비스 정책과 무관합니다.

원문복사신청을 하시면, 일부 해외 인쇄학술지의 경우 외국학술지지원센터(FRIC)에서
무료 원문복사 서비스를 제공합니다.

NDSL에서는 해당 원문을 복사서비스하고 있습니다. 위의 원문복사신청 또는 장바구니 담기를 통하여 원문복사서비스 이용이 가능합니다.

이 논문과 함께 출판된 논문 + 더보기