DOI QR코드

DOI QR Code

유방암 세포와 간암세포에 있어서 에스트로겐 수용체의 전사조절기능에 대한 Xenobiotic 핵 수용체 (Constitutive Androstane Receptor, Steroid and Xenobiotic Receptor, Peroxisome-Proliferator-Activated Receptor γ )의 영향 비교분석

Comparison and Analysis between Human Breast Cancer Cells and Hepatoma Cells for the Effects of Xenobiotic Nuclear Receptors (Constitutive Androstane Receptor, Steroid and Xenobiotic Receptor, and Peroxisome-Proliferator-Activated Receptor γ ) on the Transcriptional Activity of Estrogen Receptor

  • 민계식 (진주산업대학교 미생물공학과)
  • 발행 : 2003.06.01

초록

지금까지 estrogen 호르몬이 유방암의 발생과 진전에 관여한다는 사실을 뒷받침 할 수 있는 여러 가지 증거가 제시되어 왔지만, 암화에 관여하고 있는 estrogen의 분자생물학적 작용기전에 대해서는 아직 명확히 알려져 있지 않다. 유방암 세포의 발암현상은 다양한 핵 수용체들과 이들 각각의 신호전달경로들 사이의 기능적 상호교류 (Functional Cross-talk)에 의해 조절되는 것으로 추측되고 있다. 그러므로, 유방암세포의 성장과 증식에 관여하는 신호전달경로중에서 estrogen의 작용을 조절할 수 있는 핵 수용체를 밝혀내고, 이러한 수용체와 estrogen receptor사이에 어떠한 기능적 상호교류가 일어나는지를 규명하는 것은 암화와 관련된 estrogen의 분자생물학적 작용기전을 이해하는 데 중요한 진전을 가져올 수 있다. 따라서 본 연구의 목적은 유방암세포 내에서 estrogen의 작용이 xenobiotic nuclear receptor에 의해 조절되는지를 규명하기 위하여, 두 종류의 유방암세포인 estrogen receptor가 발현되는 MCF-7 세포와 ER의 발현이 일어나지 않는 MDA-MB-231세포를 배양하여, 에스트로겐에 의해 전사가 촉진되는 보고유전자의 발현이 CAR, SXR, 그리고 PPAR${\gamma}$에 의해서 어떻게 영향을 받는지를 조사하고 그 결과를 간암세포에서의 반응과 비교 분석하였다. 최근에 보고된 연구결과와 일치하게, xenobiotic nuclear receptor가 간세포에서 일어나는 에스트로겐 수용체의 신호전달경로에 영향을 줄 수 있음을 확인하였다. PPAR${\gamma}$를 제외한 핵 수용체 CAR와 SXR은 ER의 전사활성 효과를 현저하게 또는 어느 정도 각각 감소시켰다. Hep G2세포에서와는 달리 유방암세포에서는 조사된 세가지의 xenobiotic 핵 수용체가 ER의 전사활성에 그다지 영향을 미치지 않거나 유방암세포의 종류와 각각의 수용체에 따라서 다소 촉진하는 경향을 나타내었다. MCF-7 세포에서는 CAR와 PPAR${\gamma}$을 제외한 SXR이 ER의 transactivation 효과를 약간 촉진한 반면 MDA-MB-231세포는 SXR을 제외한 CAR와 PPAR${\gamma}$에 의해 ER의 transactivation 효과가 약간 증가되는 경향을 보였다. 이러한 결과는 유방암세포에서는 CAR, SXR, PPAR${\gamma}$과 같은 xenobiotic nuclear receptor에 의한 ER transactivation 효과가 간암세포와는 다르게 나타나며, 유방암의 종류에 따라서 endogenous CAR, SXR, PPAR${\gamma}$수용체가 다르게 발현됨으로써 이들에 대한 반응이 서로 상이한 특징을 나타낼 수 있을 것으로 사료된다. 따라서 estrogen receptor에 의해 매개되는 estrogn의 전사활성조절기전이 표적세포에 따라 다른 경로를 포함 할 수 있음을 시사한다.

The purpose of this study was to examine the effects of xenobiotic nuclear receptors, CAR, SXR, and PPAR${\gamma}$ on the transcriptional activity of estrogen receptor in human breast cancer cell lines and compare with those in human hepatoma cell line. Two different breast cancer cell lines, MCF-7 and MDA-MB-231 were cultured and effects of CAR, SXR, and PPAR${\gamma}$ on the ER-mediated transcriptional activation of synthetic (4ERE)-tk-luciferase reporter gene were analyzed. Consistent with the previous report, CAR significantly inhibited ER-mediated transactivation and SXR repressed modestly whereas the PPAR${\gamma}$ did not repress the ER-mediated transactivation. However, in breast cancer cells neither of the xenobiotic receptors repressed the ER-mediated transactivation. Instead, they tend to increase the transactivation depending on the cell type and xenobiotic nuclear receptors. In MCF-7, SXR but neither CAR nor PPAR${\gamma}$ slightly increased ER-mediated transactivation whereas in MDA-MB-231, CAR and PPAR${\gamma}$ but not SXR tend to increase the transactivation of the reporter gene. These results indicate that the effects of ER cross-talk by the CAR, SXR, and PPAR${\gamma}$ , are different in breast cancer cells from hepatoma cells. In conclusion, the transcriptional regulation by estrogen can involve different cross-talk interaction between estrogen receptor and xenobiotic nuclear receptors depending on the estrogen target cells.

키워드

참고문헌

  1. Blumberg, B. and R.M. Evans. 1998. Orphan nuclear receptors-new ligands and new possibilities. Genes Dev. 15, 3149-3155
  2. Blumberg, B., W. Jr. Sabbagh, H. Juguilon, J. Jr. Bolado, CM. van. Meter, E. S. Ong and R M. Evans. 1998. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Oev. 15, 3195-3205
  3. Clay, C. E., A. M. Namen, G. Atsumi, M. C. Willingham, K. P. High, T. E. Kute, A. J. Trimboli, A. N. Fonteh, P. A. Dawson and F. H. Chilton. 1999. Influence of J series prostaglandins on apoptosis and tumorigenesis of breast cancer cells. Carcinogenesis. 20, 1905-1911 https://doi.org/10.1093/carcin/20.10.1905
  4. Duan, R., W. Porter, I. Samudio, C. Vyhlida!, M. Kladde and S. Safe. 1999. Transcriptional activation of c-fos protooncogene by 17beta-estradiol: mech-anism of aryl hydrocarbon receptor-mediated inhi-bition. Mol. Endocrinol. 13, 1511-1521 https://doi.org/10.1210/me.13.9.1511
  5. Elstner, E., C. Muller, K. Koshizuka, E. A. Williamson, D. Park, H. Asou, P. Shintaku, J. W. Said. D. Heber and H. P. Koeffler. 1998. Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc. Natl. Acad. Sci. 21, 8806-8811
  6. Forman, B. M., I. Tzameli, H. S. Choi, J. Chen, D. Sirnha, W. Seol, R M. Evans and D. D. Moore. 1998. Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature. 8, 612-615 https://doi.org/10.1038/nmat2498
  7. Glass, C. K., J. M. Holloway, O. V. Devary and M. G. Rosenfeld. 1988. The thyroid hormone receptor binds with opposite transcriptional effects to a common sequence motif in thyroid hormone and es-trogen response elements. Cell. 29, 313-323
  8. Katzenellenbogen, B. S. and J. A Katzenellenbogen. 2000. Estrogen receptor transcription and trans-activation: Estrogen receptor alpha and estrogen receptor beta: regulation by selective estrogen receptor modulators and importance in breast cancer. Breast Cancer Res. 2, 335-344 https://doi.org/10.1186/bcr78
  9. Keller, H., F. Givel, M. Perroud and W. Wahli. 1995. Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements. Mol. Endocrinol. 9, 794-804 https://doi.org/10.1210/me.9.7.794
  10. Kharat, I. and F. Saatcioglu. 1996. Antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin are medi-ated by direct transcriptional interference with the liganded estrogen receptor. Cross-talk between aryl hydrocarbon- and estrogen-mediated signaling. J. BioI. Chem. 3, 10533-10537
  11. Kliewer, S. A, J. M. Lehmann and T. M. Willson. 1999. Orphan nuclear receptors: shifting endocrinology into reverse. Science. 30, 757-760
  12. Kraus, W. L., K. E. Weis and B. S. Katzenellenbogen. 1995. Inhibitory cross-talk between steroid hormone receptors: differential targeting of estrogen receptor in the repression of its transcriptional activity by agonist-and antagonist-occupied progestin receptors. Mol. Cell BioI. 15, 1847-1857
  13. McKay, L. I. and J. A. Cidlowski. 1998. Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antago-nism. Mol. Endocrinol. 12, 45-56 https://doi.org/10.1210/me.12.1.45
  14. Menck, H. R, J. M. Jessup, H. J. Eyre, M. P. Cunningham, A. Fremgen, G. P. Murphy and D. P. Winchester. 1997. Clinical highlights from the National Cancer Data Base. CA. Cancer J- Clin. 47, 161-170 https://doi.org/10.3322/canjclin.47.3.161
  15. Min, G., J. K. Kemper and B. Kemper. 2002. Glucocorticoid receptor-interacting protein 1 mediates ligand-independent nuclear translocation and activation of constitutive androstane receptor in vivo. J. BioI. Chem. 277, 26356-26363 https://doi.org/10.1074/jbc.M200051200
  16. Min, G., H. Kim, Y. Bae, L. Petz and J. K Kemper. 2002. Inhibitory cross-talk between estrogen receptor (ER) and constitutively activated androstane receptor (CAR). CAR inhibits ER-mediated signaling pathway by squelching p160 coactivators. J. BioI. Chem. 13, 34626-34633
  17. Moore, L. B., D. J. Parks, S, A. Jones, R. K. Bledsoe, T. G. Consler, J. B. Stimmel, B. Goodwin, C. Liddle, S. G. Blanchard, T. M. Willson, J. L. Collins and S.A. Kliewer. 2000. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J. BioI. Chem. 19, 15122-15127
  18. Nunez, S. B., J. A. Medin, O. Braissant, L. Kemp, W. Wahli, K Ozato and J. H. Segars. 1997. Retinoid X receptor and peroxisome proliferator-activated rece-ptor activate an estrogen responsive gene independent of the estrogen receptor. Mol. Cell Endocrinol. 14, 27-40
  19. Paech, K, P. Webb, G. G. Kuiper, S. Nilsson, J. Gustafsson, P. J. Kushner and T. S. Scanlan. 1997. Differential ligand activation of estrogen receptors ERalpha and ERbeta at API sites. Science. 277, 1508-1510 https://doi.org/10.1126/science.277.5331.1508
  20. Ricci, M. S., D. G. Toscano, C. J. Mattingly and W. A. Jr. Toscano. 1999. Estrogen receptor reduces CYP1A1 induction in cultured human endometrial cells. J. BioI. Chem. 5, 3430-3438
  21. Seol, W., B. Hanstein, M. Brown and D. D. Moore.1998. Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner). Mol. Endocrinoi. 12, 1551-1557 https://doi.org/10.1210/me.12.10.1551
  22. Smith C. L. 1998. Cross-talk between peptide growth factor and estrogen receptor signaling pathways. BioI. Reprod. 58, 627-632 https://doi.org/10.1095/biolreprod58.3.627
  23. Sugatani, J., H. Kojima, A. Veda, S. Kakizaki, K Yoshinari, Q. H. Gong, I. S. Owens, M. Negishi and T. Sueyoshi. 2001. The phenobarbital response en-hancer module in the human bilirubin UDP-glucuronosyltransferase UGTlAl gene and regulation by the nuclear receptor CAR. Hepatology. 33, 1232-1238 https://doi.org/10.1053/jhep.2001.24172
  24. Tzameli, I., P. Pissios, E. G. Schuetz and D. D. Moore. 2000. The xenobiotic compound 1,4-bis[2-(3,5dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR. Mol. Cell BioI. 20, 2951-2958 https://doi.org/10.1128/MCB.20.9.2951-2958.2000
  25. Wei. P., J. Zhang. M. Egan-Hafley, S. Liang and D. D. Moore. 2000. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature. 19, 920-923

피인용 문헌

  1. Different Modulation of ER-Mediated Transactivation by Xenobiotic Nuclear Receptors Depending on the Estrogen Response Elements and Estrogen Target Cell Types vol.1091, pp.1, 2006, https://doi.org/10.1196/annals.1378.071