Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Cell Growth of BG-1 Ovarian Cancer Cells was Promoted by 4-Tert-octylphenol and 4-Nonylphenol via Downregulation of TGF-β Receptor 2 and Upregulation of c-myc

  • Park, Min-Ah (Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University) ;
  • Hwang, Kyung-A (Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University) ;
  • Lee, Hye-Rim (Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University) ;
  • Yi, Bo-Rim (Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University) ;
  • Choi, Kyung-Chul (Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University)
  • Received : 2011.11.02
  • Accepted : 2011.11.13
  • Published : 2011.12.01
Download PDF
⟨ Previous Next ⟩

Abstract

Transforming growth factor ${\beta}$ (TGF-${\beta}$) is involved in cellular processes including growth, differentiation, apoptosis, migration, and homeostasis. Generally, TGF-${\beta}$ is the inhibitor of cell cycle progression and plays a role in enhancing the antagonistic effects of many growth factors. Unlike the antiproliferative effect of TGF-${\beta}$, E2, an endogeneous estrogen, is stimulating cell proliferation in the estrogen-dependent organs, which are mediated via the estrogen receptors, $ER{\alpha}$ and $ER{\beta}$, and may be considered as a critical risk factor in tumorigenesis of hormone-responsive cancers. Previous researches reported the cross-talk between estrogen/$ER{\alpha}$ and TGF-${\beta}$ pathway. Especially, based on the E2-mediated inhibition of TGF-${\beta}$ signaling, we examined the inhibition effect of 4-tert-octylphenol (OP) and 4-nonylphenol (NP), which are well known xenoestrogens in endocrine disrupting chemicals (EDCs), on TGF-${\beta}$ signaling via semi-quantitative reverse-transcription PCR. The treatment of E2, OP, or NP resulted in the downregulation of TGF-${\beta}$ receptor2 (TGF-${\beta}$ R2) in TGF-${\beta}$ signaling pathway. However, the expression level of TGF-${\beta}1$ and TGF-${\beta}$ receptor1 (TGF-${\beta}$ R1) genes was not altered. On the other hand, E2, OP, or NP upregulated the expression of a cell-cycle regulating gene, c-myc, which is a oncogene and a downstream target gene of TGF-${\beta}$ signaling pathway. As a result of downregulation of TGF-${\beta}$ R2 and the upregulation of c-myc, E2, OP, or NP increased cell proliferation of BG-1 ovarian cancer cells. Taken together, these results suggest that E2 and these two EDCs may mediate cancer cell proliferation by inhibiting TGF-${\beta}$ signaling via the downregulation of TGF-${\beta}$ R2 and the upregulation of c-myc oncogene. In addition, it can be inferred that these EDCs have the possibility of tumorigenesis in estrogen-responsive organs by certainly representing estrogenic effect in inhibiting TGF-${\beta}$ signaling.

Keywords

References

  1. Asimakopoulos, A.G., Thomaidis, N.S. and Koupparis, M.A. (2011). Recent trends in biomonitoring of bisphenol A, 4-toctylphenol, and 4-nonylphenol. Toxicol. Lett. In press.
  2. Band, A.M. and Laiho, M. (2011). Crosstalk of TGF-beta and estrogen receptor signaling in breast cancer. J. Mammary Gland Biol. Neoplasia, 16, 109-115. https://doi.org/10.1007/s10911-011-9203-7
  3. Chen, C.R., Kang, Y., Siegel, P.M. and Massague, J. (2002). E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell, 110, 19-32. https://doi.org/10.1016/S0092-8674(02)00801-2
  4. Choi, K.C. and Jeung, E.B. (2003). The biomarker and endocrine disruptors in mammals. J. Reprod. Dev., 49, 337-345. https://doi.org/10.1262/jrd.49.337
  5. Choi, S.M., Yoo, S.D. and Lee, B.M. (2004). Toxicological characteristics of endocrine-disrupting chemicals: developmental toxicity, carcinogenicity, and mutagenicity. J. Toxicol. Environ. Health B Crit. Rev., 7, 1-24. https://doi.org/10.1080/10937400490253229
  6. Diamanti-Kandarakis, E., Bourguignon, J.P., Giudice, L.C., Hauser, R., Prins, G.S., Soto, A.M., Zoeller, R.T. and Gore, A.C. (2009). Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr. Rev., 30, 293-342. https://doi.org/10.1210/er.2009-0002
  7. Doisneau-Sixou, S.F., Sergio, C.M., Carroll, J.S., Hui, R., Musgrove, E.A. and Sutherland, R.L. (2003). Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells. Endocr. Relat. Cancer, 10, 179-186. https://doi.org/10.1677/erc.0.0100179
  8. Dunfield, L.D. and Nachtigal, M.W. (2003). Inhibition of the antiproliferative effect of TGFbeta by EGF in primary human ovarian cancer cells. Oncogene, 22, 4745-4751. https://doi.org/10.1038/sj.onc.1206617
  9. Elliott, R.L. and Blobe, G.C. (2005). Role of transforming growth factor Beta in human cancer. J. Clin. Oncol., 23, 2078-2093. https://doi.org/10.1200/JCO.2005.02.047
  10. Feng, X.H. and Derynck, R. (2005). Specificity and versatility in tgf-beta signaling through Smads. Annu. Rev. Cell Dev. Biol., 21, 659-693. https://doi.org/10.1146/annurev.cellbio.21.022404.142018
  11. Gantus, M.A., Alves, L.M., Stipursky, J., Souza, E.C., Teodoro, A.J., Alves, T.R., Carvalho, D.P., Martinez, A.M., Gomes, F.C. and Nasciutti, L.E. (2011). Estradiol modulates TGF-beta1 expression and its signaling pathway in thyroid stromal cells. Mol. Cell Endocrinol., 337, 71-79. https://doi.org/10.1016/j.mce.2011.02.001
  12. Gomis, R.R., Alarcon, C., Nadal, C., Van Poznak, C. and Massague, J. (2006). C/EBPbeta at the core of the TGFbeta cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell, 10, 203-214. https://doi.org/10.1016/j.ccr.2006.07.019
  13. Goto, N., Hiyoshi, H., Ito, I., Tsuchiya, M., Nakajima, Y. and Yanagisawa, J. (2011). Estrogen and antiestrogens alter breast cancer invasiveness by modulating the transforming growth factor-beta signaling pathway. Cancer Sci., 102, 1501-1508. https://doi.org/10.1111/j.1349-7006.2011.01977.x
  14. Hagiwara, H., Sugizaki, T., Tsukamoto, Y., Senoh, E., Goto, T. and Ishihara, Y. (2008). Effects of alkylphenols on bone metabolism in vivo and in vitro. Toxicol. Lett., 181, 13-18. https://doi.org/10.1016/j.toxlet.2008.06.863
  15. Hill, J.J., Tremblay, T.L., Cantin, C., O'Connor-McCourt, M., Kelly, J.F. and Lenferink, A.E. (2009). Glycoproteomic analysis of two mouse mammary cell lines during transforming growth factor (TGF)-beta induced epithelial to mesenchymal transition. Proteome. Sci., 7, 2. https://doi.org/10.1186/1477-5956-7-2
  16. Hwang, K.A., Park, S.H., Yi, B.R. and Choi, K.C. (2011). Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Lab. Anim. Res., 27, 99-107. https://doi.org/10.5625/lar.2011.27.2.99
  17. Ito, I., Hanyu, A., Wayama, M., Goto, N., Katsuno, Y., Kawasaki, S., Nakajima, Y., Kajiro, M., Komatsu, Y., Fujimura, A., Hirota, R., Murayama, A., Kimura, K., Imamura, T. and Yanagisawa, J. (2010). Estrogen inhibits transforming growth factor beta signaling by promoting Smad2/3 degradation. J. Biol. Chem., 285, 14747-14755. https://doi.org/10.1074/jbc.M109.093039
  18. Khan, S.A., Rogers, M.A., Khurana, K.K., Meguid, M.M. and Numann, P.J. (1998). Estrogen receptor expression in benign breast epithelium and breast cancer risk. J. Natl. Cancer Inst., 90, 37-42. https://doi.org/10.1093/jnci/90.1.37
  19. Kim, D.Y., Kim, M.J., Kim, H.B., Lee, J.W., Bae, J.H., Kim, D.W., Kang, C.D. and Kim, S.H. (2011). Suppression of multidrug resistance by treatment with TRAIL in human ovarian and breast cancer cells with high level of c-Myc. Biochim. Biophys. Acta., 1812, 796-805. https://doi.org/10.1016/j.bbadis.2011.04.004
  20. Kochukov, M.Y., Jeng, Y.J. and Watson, C.S. (2009). Alkylphenol xenoestrogens with varying carbon chain lengths differentially and potently activate signaling and functional responses in GH3/B6/F10 somatomammotropes. Environ Health Perspect., 117, 723-730. https://doi.org/10.1289/ehp.0800182
  21. Massague, J., Seoane, J. and Wotton, D. (2005). Smad transcription factors. Genes. Dev., 19, 2783-2810. https://doi.org/10.1101/gad.1350705
  22. Massague, J. (2008). TGFbeta in Cancer. Cell, 134, 215-230. https://doi.org/10.1016/j.cell.2008.07.001
  23. Matsuda, T., Yamamoto, T., Muraguchi, A. and Saatcioglu, F. (2001). Cross-talk between transforming growth factor-beta and estrogen receptor signaling through Smad3. J. Biol. Chem., 276, 42908-42914. https://doi.org/10.1074/jbc.M105316200
  24. McCaffrey, T.A., Consigli, S., Du, B., Falcone, D.J., Sanborn, T.A., Spokojny, A.M. and Bush, H.L., Jr. (1995). Decreased type II/type I TGF-beta receptor ratio in cells derived from human atherosclerotic lesions. Conversion from an antiproliferative to profibrotic response to TGF-beta1. J. Clin. Invest., 96, 2667-2675. https://doi.org/10.1172/JCI118333
  25. Nilsson, E.E. and Skinner, M.K. (2002). Role of transforming growth factor beta in ovarian surface epithelium biology and ovarian cancer. Reprod. Biomed. Online, 5, 254-258. https://doi.org/10.1016/S1472-6483(10)61828-7
  26. Osada, H., Yoshitake, Y., Ikeda, T., Ishigaki, Y., Takata, T., Tomosugi, N., Sasaki, H. and Yonekura, H. (2011). Ultraviolet Binduced expression of amphiregulin and growth differentiation factor 15 in human lens epithelial cells. Mol. Vis., 17, 159-169.
  27. Park, M.A., Hwang, K.A., Lee, H.R., Yi, B.R., Jeung, E.B. and Choi, K.C. (2011). Cell growth of BG-1 ovarian cancer cells was promoted by di-n-butyl phthalate and hexaboromocyclododecane via upregulation of cyclin D and cell cycle-dependent kinase-4 genes. Mol. Med. Report. In press.
  28. Park, S.H., Kim, K.Y., An, B.S., Choi, J.H., Jeung, E.B., Leung, P.C. and Choi, K.C. (2009). Cell growth of ovarian cancer cells is stimulated by xenoestrogens through an estrogen-dependent pathway, but their stimulation of cell growth appears not to be involved in the activation of the mitogen-activated protein kinases ERK-1 and p38. J. Reprod. Dev., 55, 23-29. https://doi.org/10.1262/jrd.20094
  29. Pedram, A., Razandi, M. and Levin, E.R. (2006). Nature of functional estrogen receptors at the plasma membrane. Mol. Endocrinol., 20, 1996-2009. https://doi.org/10.1210/me.2005-0525
  30. Regan, M.M., Viale, G., Mastropasqua, M.G., Maiorano, E., Golouh, R., Carbone, A., Brown, B., Suurkula, M., Langman, G., Mazzucchelli, L., Braye, S., Grigolato, P., Gelber, R.D., Castiglione- Gertsch, M., Price, K.N., Coates, A.S., Goldhirsch, A. and Gusterson, B. (2006). Re-evaluating adjuvant breast cancer trials: assessing hormone receptor status by immunohistochemical versus extraction assays. J. Natl. Cancer Inst., 98, 1571-1581. https://doi.org/10.1093/jnci/djj415
  31. Schuster, N. and Krieglstein, K. (2002). Mechanisms of TGF-betamediated apoptosis. Cell Tissue Res., 307, 1-14. https://doi.org/10.1007/s00441-001-0479-6
  32. Shanle, E.K. and Xu, W. (2011). Endocrine disrupting chemicals targeting estrogen receptor signaling: identification and mechanisms of action. Chem. Res. Toxicol., 24, 6-19. https://doi.org/10.1021/tx100231n
  33. Terasaka, S., Inoue, A., Tanji, M. and Kiyama, R. (2006). Expression profiling of estrogen-responsive genes in breast cancer cells treated with alkylphenols, chlorinated phenols, parabens, or bis- and benzoylphenols for evaluation of estrogenic activity. Toxicol. Lett., 163, 130-141. https://doi.org/10.1016/j.toxlet.2005.10.005
  34. Theriault, B.L. and Nachtigal, M.W. (2011). Human ovarian cancer cell morphology, motility, and proliferation are differentially influenced by autocrine TGFbeta superfamily signalling. Cancer Lett., 313, 108-121. https://doi.org/10.1016/j.canlet.2011.08.033
  35. Watanabe, J., Kamata, Y., Seo, N., Okayasu, I. and Kuramoto, H. (2007). Stimulatory effect of estrogen on the growth of endometrial cancer cells is regulated by cell-cycle regulators. J. Steroid. Biochem. Mol. Biol., 107, 163-171. https://doi.org/10.1016/j.jsbmb.2007.03.045
  36. Yi, B.R., Kang, N.H., Hwang, K.A., Kim, S.U., Jung, E.B. and Choi, K.C. (2011). Antitumor Therapeuic Effects of Cytosinf Deaminase and Interferon-â Against Endometrial Cancer Cells Using Genetically Ebngineered Stem Cells In Vitro. Anticancer Reserch, 31, 2853-2861.
  37. Yilmaz, M., Maass, D., Tiwari, N., Waldmeier, L., Schmidt, P., Lehembre, F. and Christofori, G. (2011). Transcription factor Dlx2 protects from TGFbeta-induced cell-cycle arrest and apoptosis. EMBO. J., 30, 4489-4499. https://doi.org/10.1038/emboj.2011.319