$\require{mediawiki-texvc}$
  • 검색어에 아래의 연산자를 사용하시면 더 정확한 검색결과를 얻을 수 있습니다.
  • 검색연산자
검색연산자 기능 검색시 예
() 우선순위가 가장 높은 연산자 예1) (나노 (기계 | machine))
공백 두 개의 검색어(식)을 모두 포함하고 있는 문서 검색 예1) (나노 기계)
예2) 나노 장영실
| 두 개의 검색어(식) 중 하나 이상 포함하고 있는 문서 검색 예1) (줄기세포 | 면역)
예2) 줄기세포 | 장영실
! NOT 이후에 있는 검색어가 포함된 문서는 제외 예1) (황금 !백금)
예2) !image
* 검색어의 *란에 0개 이상의 임의의 문자가 포함된 문서 검색 예) semi*
"" 따옴표 내의 구문과 완전히 일치하는 문서만 검색 예) "Transform and Quantization"
쳇봇 이모티콘
안녕하세요!
ScienceON 챗봇입니다.
궁금한 것은 저에게 물어봐주세요.

논문 상세정보

초록

많은 암세포에 선택적 세포독성을 나타내는 TNF-related apoptosis-inducing ligand (TRAIL)는 유효한 항암제로서 사용될 수 있지만, TRAIL에 내성을 나타내는 암세포에는 TRAIL-sensitization의 방법이 필요하다. 사람 대장암 세포인 KMl2 세포도 TRAIL에 내성을 나타낸다. 본 연구에서는 KMl2세포의 TRAIL 내성에 대한 새로운 표적 분자의 발굴과 이를 토대로 한 새로운 내성극복 방법을 연구하였다. 새로운 TRAIL sensitizer로서 quercetin을 발굴하고, 이를 KMl2세포에 TRAIL과 병용 처리하여 TRAIL의 효과증강을 시도하였다. KMl2세포에서 quercetin은 c-FLTP의 발현을 감소시키고, DNA-PK/Akt 신호전달경로를 억제하므로서, death receptors (DR4/DR5) 발현을 증강시켰다. 또한 caspases (caspase 3, -8 및 -9)활성 증강과 PARP cleavage, 이에 따른 Bax의 발현을 증강시키는 기전으로 TRAIL에 의한 apoptosis를 증대시키는 활성이 있음을 밝혔다. 즉 quercetin이 KMl2세포의 TRAIL-sensitization에 사용될 수 있음을 제시하였다. 이러한 연구 결과는 대장암의 치료 시 TRAIL과 quercetin병용하므로서 치료 효과를 높일 수 있는 새로운 약제 병용 방법을 제시하였고, 다른 TRAIL 내성 종양에 응용 될 수 있음을 시사하였다.

Abstract

Many cancer cells are sensitive to the TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. However, some cancer cells show either partial or complete resistance to TRAIL. Human colon carcinoma KM12 cells have been shown to be insensitive to TRAIL-induced apoptosis. To overcome TRAIL resistance in KM12 cells, we targeted key anti-apoptotic molecules involved in the modulation of TRAIL resistance in the cells, and evaluated the effects of quercetin as a TRAIL sensitizer in the cells. We found that quercetin acted in synergy with TRAIL to enhance TRAIL-induced apoptosis in KM12 cells by the down-regulation of c-FLIP and DNA-PKcs/Akt and up-regulation of death receptors (DR4/DR5), which led to the enhancement of TRAIL-mediated activation of caspases and subsequent cleavage of PARP, as well as up-regulation of Bax. These findings suggest that the DNA-PKcs/Akt signaling pathway, as well as c-FLIP, play essential roles in regulating cells in the escape from TRAIL-induced apoptosis. Based on these results, this study provides a potential application of quercetin in combination with TRAIL in the treatment of human colon cancer.

참고문헌 (42)

  1. Almasan, A and A Ashkenazi. 2003. Apo2LjTRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev. 14, 337-348 
  2. Asakuma, J., M. Sumitomo, T. Asano, T. Asano, and M. Hayakawa. 2003. Selective Akt inactivation and tumor necrosis actor-related apoptosis-inducing ligand sensitization of renal cancer cells by low concentrations of paclitaxel. Cancer Res. 63, 1365-1370 
  3. Downward, J. 2004. PI 3-kinase, Akt and cell survival. Semin. Cell Dev. BioI. 15, 177-182 
  4. Dragoi, A M., X. Fu, S. Ivanov, P. Zhang, 1. Sheng, D. Wu, G. C. Li, and W. M. Chu. 2005. DNA-PKcs, but not TLR9, is required for activation of Akt by CpG-DNA EMBO J. 24, 779-789 
  5. Dyer, M. J., M. MacFarlane, and G. M. Cohen. 2007. Barriers to effective TRAIL-targeted therapy of malignancy. J. Clin. Oncol. 25, 4505-4506 
  6. Elnemr, A, T. Ohta, A Yachie, M. Kayahara, H. Kitagawa, T. Fujimura, I. Ninomiya, S. Fushida, G. I. Nishimura, K. Shimizu, and K. Miwa. 2001. Human pancreatic cancer cells disable function of Fas receptors at several levels in Fas signal transduction pathway. Int. J. Oncol. 18, 311-316 
  7. Feng, J., J. Park, P. Cron, D. Hess, and B. A Hemmings. 2004. Identification of a PKB / Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J. Biol. Chem. 279, 41189-41196 
  8. Fulda, S., I. Jeremias, and K. M. Debatin. 2004. Cooperation of betulinic acid and TRAIL to induce apoptosis in tumor cells. Oncogene 23, 7611-7620 
  9. Gamet-Payrastre, L., S. M. Manenti, P. Gratacap, J. Tulliez, H. Chap, and B. Payrastre. 1999. Flavonoids and the inhibition of PKC and PI 3-kinase. Gen. Pharmacol. 32, 279-286 
  10. Gerhauser, C. 2008. Cancer chemopreventive potential of apples, apple juice, and apple components. Planta Med. 74, 1608-1624 
  11. Gorlick R and J. R Bertino. 1999. Drug resistance in colon cancer. Semin. Oncol. 26, 606-611 
  12. Izzard, R A, S. P. Jackson, and G. C. Smith. 1999. Competitive and noncompetitive inhibition of the DNA-dependent protein kinase. Cancer Res. 59, 2581-2586 
  13. Kennedy, S. G., E. S. KandeL T. K. Cross, and N. Hay. 1999. Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol. Cell BioI. 19, 5800-5810 
  14. Kim, S. H, J. HUm, D. W. Kim, B. H Kwon, D. W. Kim, B. S. Chung, and C. D. Kang. 2000. Potentiation of chemosensitivity in multidrug-resistant human leukemia CEM cells by inhibition of DNA-dependent protein kinase using wortmannin. Leuk. Res. 24, 917-925 
  15. Kim, Y. H, D. H Lee, J. H Jeong, Z. S. Guo, and Y. J. Lee. 2008. Quercetin augments TRAIL-induced apoptotic death: involvement of the ERK signal transduction pathway. Biochem. Pharmacol. 75, 1946-1958 
  16. Kim, Y. Hand Y. J. Lee. 2007. TRAIL apoptosis is enhanced by quercetin through Akt dephosphorylation. J. Cell Biochem. 100, 998-1009 
  17. Krueger, A, S. Baumann, P. H Krammer, and S. Kirchhoff. 2001. FUCE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Mol. Cell Biol. 21, 8247-8254 
  18. Kruyt, F. A 2008. TRAIL and cancer therapy. Cancer Lett. 263, 14-25 
  19. Kuo, P. L., Y. L. Hsu, T. C. Lin, and C. C. Lin. 2005. The antiproliferative activity of prodelphidin B-2' 3'-0-gallate from green tea leaf is through cell cycle arrest and Fas-mediated apoptotic pathway in A549 cells. Food Chem. Toxicol. 43, 315-323 
  20. Kurbanov, B. M., L. F. Fecker, C. C. Geilen, W. Sterry, and J. Eberle. 2007. Resistance of melanoma cells to TRAIL does not result from upregulation of antiapoptotic proteins by NF-kappa B but is related to downregulation of initiator caspases and DR4. Oncogene 26, 3364-3377 
  21. Lane, D., V. Robert, R Grondin, C. Rancourt, and A Piche. 2007. Malignant ascites protect against TRAIL-induced apoptosis by activating the PI3K/ Akt pathway in human ovarian carcinoma cells. Int. J. Cancer 21, 1227-1237 
  22. Larribere, 1., M. Khaled, S. Tartare-Deckert, R Busca, F. Luciano, K. Bille, G. Valony, A Eychene, P. Auberger, J. P. Ortonne, R Ballotti, and C. Bertolotto. 2004. PI3K mediates protection against TRAIL-induced apoptosis in primary human melanocytes. Cell Death Differ. 11, 1084-1091 
  23. Lee, S. H, H S. Kim, S. Y. Kim, Y. S. Lee, W. S. Park S. H Kim, J. Y. Lee, and J. Y. Nam. 2003. Increased expression of FUP, an inhibitor of Fas-mediated apoptosis, in stomach cancer. APMIS 111, 309-314 
  24. Merino, D., N. Lalaoui, A Morizot, E. Solary, and O. Micheau. 2007. TRAIL in cancer therapy: present and future challenges. Expert Opin. Ther. Targets 11, 1299-1314 
  25. Micheau, 0., M. Thome, P. Schneider, N. Holler, J. Tschopp, D. W. Nicholson, C. Briand, and M. G. Grutter. 2002. The long form of FUP is an activator of caspase-8 at the Fas death-inducing signaling complex. J. Biol. Chem. 277, 45162-45171 
  26. Nam, S. Y., G. A Jung, G. C. Hur, H. Y. Chung, W. H. Kim, D. W. SeoL and B. 1. Lee. 2003. Upregulation of FUP(S) by Akt, a possible inhibition mechanism of TRAIL-induced apoptosis in human gastric cancers. Cancer Sci. 94, 1066-1073 
  27. Palacios, C., R Yerbes, and A Lopez-Rivas. 2006. Flavopiridol induces cellular FUCE-inhibitory protein degradation by the proteasome and promotes TRAIL-induced early signaling and apoptosis in breast tumor cells. Cancer Res. 66, 8858-8869 
  28. Psahoulia, F. H., K. G. Drosopoulos, L. Doubravska, L. Andera, and A Pintzas. 2007. Quercetin enhances TRAIL-mediated apoptosis in colon cancer cells by inducing the accumulation of death receptors in lipid rafts. Mol. Cancer Ther. 6, 2591-2599 
  29. Rieger, L B. Frank M. Weller, and W. Wick. 2007. Mechanisms of resistance of human glioma cells to Apo2 ligand/TNF-related apoptosis-inducing ligand. Cell Physiol. Biochem. 20, 23-34 
  30. Russo, M., P. Nigro, R Rosiello, R D' Arienzo, and G. L. Russo. 2007. Quercetin enhances CD95- and TRAIL-induced apoptosis in leukemia cell lines. Leukemia 21, 1130-1133 
  31. Siegelin, M. D., D. E. Reuss, A HabeL A Rami, and A von Deimling. 2009. Quercetin promotes degradation of survivin and thereby enhances death-receptor-mediated apoptosis in glioma cells. Neuro. Oncol. 11, 122-131 
  32. Siegmund, D., P. Hadwiger, K. Pfizenmaier, H P. Vornlocher, and H Wajant. 2002. Selective inhibition of FUCE-like inhibitory protein expression with small interfering RNA oligonucleotides is sufficient to sensitize tumor cells for TRAIL-induced apoptosis. Mol. Med. 8, 725-732 
  33. Shi, RX., C. N. Ong, and H M. Shen. 2004. Luteolin sensitizes tumor necrosis factor-alpha apoptosis in human tumor cells. Oncogene 23, 7712-7721 
  34. Syed, V., K. Mukherjee, S. Godoy-Tundidor, and S. M. Ho. 2007. Progesterone induces apoptosis in TRAIL-resistant ovarian cancer cells by circumventing C-FUPL overexpression. J. Cell Biochem. 102, 442-452 
  35. Thakkar, H, X. Chen, F. Tyan, S. Gim, H Robinson, C. Lee, S. K. Pandey, C. Nwokorie, N. Onwudiwe, and R K. Srivastava. 2001. Pro-survival function of Akt/ protein kinase B in prostate cancer cells. Relationship with TRAIL resistance. J. Biol. Chem. 276, 38361-38369 
  36. Tian, X., G. Chen, H Xing, D. Weng, Y. Guo, and D. Ma. 2007. The relationship between the down-regulation of DNA-PKcs or Ku70 and the chemosensitization in human cervical carcinoma cell line HeLa. Oncol. Rep.18, 927-932 
  37. Tomasetti, M., M. R Rippo, R Alleva, S. Moretti, L. Andera, J. Neuzil, and A Procopio. 2004. a-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells. Br. J. Cancer 90, 1644-1653 
  38. Uchida, M., M. Iwase, S. Takaoka, S. Yoshiba, G. Kondo, H Watanabe, M. Ohashi, M. Nagumo, and S. Shintani. 2007. Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors. Int. J. Oneal. 30, 1163-1171 
  39. Ullenhag, G. L A. Mukherjee, N. F. Watson, A. HAl-Attar, J. H Scholefield, and 1. G. Durrant. 2007. Overexpression of FLIPL is an independent marker of poor prognosis in colorectal cancer patients. Clin. Cancer Res. 13, 5070-5075 
  40. Weterings, E. and D. J. Chen. 2007. DNA-dependent protein kinase in nonhomologous end joining: a lock with multiple keys? J. Cell Biol. 179, 183-186 
  41. Yagita, H, K, Takeda, Y. M., Hayakawa, J. Smyth, and K Okumura. 2004. TRAIL and its receptors as targets for cancer therapy. Cancer Sci. 95, 777-783 
  42. Zhong, X. and A. R. Safa. 2007. Phosphorylation of RNA helicase A by DNA-dependent protein kinase is indispensable for expression of the MDR1 gene product P-glycoprotein in multidrug-resistant human leukemia cells. Biochemistry 46, 5766-5775 

이 논문을 인용한 문헌 (0)

  1. 이 논문을 인용한 문헌 없음

원문보기

원문 PDF 다운로드

  • ScienceON :
  • KCI :

원문 URL 링크

원문 PDF 파일 및 링크정보가 존재하지 않을 경우 KISTI DDS 시스템에서 제공하는 원문복사서비스를 사용할 수 있습니다. (원문복사서비스 안내 바로 가기)

상세조회 0건 원문조회 0건

DOI 인용 스타일