Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Establishment of Reporter Cell Lines that Monitor Activities of Hypoxia Inducible Factor-1, P53 and Nur77 for Assessment of Carcinogenicity

저산소유도인자 HIF-1, 암 억제인자 P53과 고아 핵수용체 Nur77의 발현을 지표로 하는 발암독성예측 세포주의 개발

  • Hong, Il (College of Pharmacy, Seoul National University) ;
  • Seo, Hee-Won (College of Pharmacy, Seoul National University) ;
  • Lee, Min-Ho (College of Pharmacy, Seoul National University) ;
  • Kim, Ji-Won (College of Pharmacy, Seoul National University) ;
  • Chung, Jin-Ho (College of Pharmacy, Seoul National University) ;
  • Lee, Byung-Hoon (College of Pharmacy, Seoul National University) ;
  • Lee, Mi-Ock (College of Pharmacy, Seoul National University)
  • Published : 2007.09.30
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Abstract

Evaluation of potentials of chemicals to alter expression of genes that are involved in carcinogenesis may serve useful tools in toxicological research. In this investigation, we developed reporter cell lines that expressed luciferase in response to transactivation of hypoxia inducible factor-1, P53 tumor suppressor and Nur77 of which roles have been well established in cancer development and progression. Whereas these reporter cell lines displayed low constitutive backgrounds, the reporter activities were significantly enhanced in response to $desferriosamine/CoCl_2$, adriamycin or 6-mercaptopurine, which are hypoxia mimicking chemicals, P53 activator or Nur77 inducer, respectively. The activation of the reporter was time- and dose-dependent. Known tumor initiators and promoters, such as phorbol 12-myristate 13-acetate and phorbol 12, 13-dicaprinate induced the reporter activity at as low as 10nM in these stable cell lines. Further, known anti-tumor promoters, such as ascorbic acid and ${\beta}-carotene$ repressed the reporter activities. These results indicate that our stable reporter cell lines could serve as a useful system for rapid assessment of carcinogenicity of toxic chemicals.

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References

  1. Ahlstrom, M., Pekkinen, M., Huttunen, M. and Lamberg- Allardt, C. (2005). Dexamethasone down-regulates cAMPphosphodiesterase in human osteosarcoma cells. Biochem. Pharmacol., 69, 267-275 https://doi.org/10.1016/j.bcp.2004.09.012
  2. Arni, P. (1989). Review on the genotoxic activity of thioacetamide. Mutat. Res., 221, 153-162 https://doi.org/10.1016/0165-1110(89)90003-1
  3. Arnold, D.L. and Boyes, B.G. (1989). The toxicological effects of saccharin in short-term genotoxicity assays. Mutat. Res., 221, 69-132 https://doi.org/10.1016/0165-1110(89)90001-8
  4. Auvinen, M., Paasinen, A., Andersson, L.C. and Holtta, E. (1992). Ornithine decarboxylase activity is critical for cell transformation. Nature, 360, 355-358 https://doi.org/10.1038/360355a0
  5. Bae, S.H., Jeong, J.W., Park, J.A., Kim, S.H., Bae, M.K., Choi, S.J. and Kim, K.W. (2004). Sumoylation increases HIF-1alpha stability and its transcriptional activity. Biochem. Biophys. Res. Commun., 324, 394-400 https://doi.org/10.1016/j.bbrc.2004.09.068
  6. Baek, J.H., Mahon, P.C., Oh, J., Kelly, B., Krishnamachary, B., Pearson, M., Chan, D.A., Giaccia, A.J. and Semenza, G.L. (2005). OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha. Mol. Cell., 17, 503-512 https://doi.org/10.1016/j.molcel.2005.01.011
  7. Barrett, J.C., Hesterberg, T.W. and Thomassen, D.G. (1984). Use of cell transformation systems for carcinogenicity testing and mechanistic studies of carcinogenesis. Pharmacol. Rev., 36, 53-70
  8. Begley, T.J. and Samson, L.D. (2004). Network responses to DNA damaging agents. DNA Repair., 3, 1123-1132 https://doi.org/10.1016/j.dnarep.2004.03.013
  9. Berra, E., Benizri, E., Ginouves, A., Volmat, V., Roux, D. and Pouyssegur, J. (2003). HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF- 1alpha in normoxia. EMBO J., 22, 4082-4090 https://doi.org/10.1093/emboj/cdg392
  10. Bradner, W.T. (2001). Mitomycin C: a clinical update. Cancer Treat. Rev., 27, 35-50 https://doi.org/10.1053/ctrv.2000.0202
  11. Burke, B., Eady, E.A. and Cunliffe, W.J. (1983). Benzoyl peroxide versus topical erythromycin in the treatment of acne vulgaris. Br. J. Dermatol., 108, 199-204 https://doi.org/10.1111/j.1365-2133.1983.tb00063.x
  12. Chan, D.A., Sutphin, P.D., Denko, N.C. and Giaccia, A.J. (2002). Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1$\alpha$. J. Biol. Chem., 277, 40112-40117 https://doi.org/10.1074/jbc.M206922200
  13. Chan, K.S., Carbajal, S., Kiguchi, K., Clifford, J., Sano, S. and DiGiovanni, J. (2004). Epidermal growth factor receptor- mediated activation of Stat3 during multistage skin carcinogenesis. Cancer Res., 64, 2382-2389 https://doi.org/10.1158/0008-5472.CAN-03-3197
  14. Choi, J.W., Park, S.C., Kang, G.H., Liu, J.O. and Youn, H.D. (2004). Nur77 activated by hypoxia-inducible factor-1alpha overproduces proopiomelanocortin in von Hippel-Lindaumutated renal cell carcinoma. Cancer Res., 64, 35-39 https://doi.org/10.1158/0008-5472.CAN-03-0145
  15. Cioffi, C.L., Liu, Q.X., Kosinski, P.A., Garay, M. and Bowen, B.R. (2003). Differential regulation of HIF-1 alpha prolyl-4- hydroxylase genes by hypoxia in human cardiovascular cells. Biochem. Biophys. Res. Commun., 303, 947-953 https://doi.org/10.1016/S0006-291X(03)00453-4
  16. Cohen, B.A. (2001). Clinical applications of new cerebrospinal fluid analytic techniques for the diagnosis and treatment of central nervous system infections. Curr. Neurol. Neurosci. Rep., 1, 518-525 https://doi.org/10.1007/s11910-001-0056-0
  17. Dequiedt, F., Van Lint, J., Lecomte, E., Van Duppen, V., Seufferlein, T., Vandenheede, J.R., Wattiez, R. and Kettmann, R. (2005). Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor-induced Nur77 expression and apoptosis. J. Exp. Med., 201, 793- 804 https://doi.org/10.1084/jem.20042034
  18. Ema, M., Taya, S., Yokotani, N., Sogawa, K., Matsuda, Y. and Fujii-Kuriyama, Y. (1997). A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc. Natl. Acad. Sci., 94, 4273-4278
  19. Erez, N., Milyavsky, M., Eilam, R., Shats, I., Goldfinger, N. and Rotter, V. (2003). Expression of prolyl-hydroxylase-1 (PHD1/EGLN2) suppresses hypoxia inducible factor-1alpha activation and inhibits tumor growth. Cancer Res., 63, 8777-8783
  20. Farkas, A., Kemény, L., Szöny, B.J., Bata-Csörgö, Z., Pivarcsi, A., Kiss, M., Széll, M., Koreck, A. and Dobozy, A. (2001). Dithranol upregulates IL-10 receptors on the cultured human keratinocyte cell line HaCaT. Inflamm. Res., 50, 44-49 https://doi.org/10.1007/s000110050723
  21. Fang, M.Z., Kim, D.Y., Lee, H.W. and Cho, M.H. (2001). Improvement of in vitro two-stage transformation assay and determination of the promotional effect of cadmium. Toxicol. In Vitro, 15, 225-231 https://doi.org/10.1016/S0887-2333(01)00012-1
  22. Fraser, M., Chan, S.L., Chan, S.S., Fiscus, R.R. and Tsang, B.K. (2006). Regulation of p53 and suppression of apoptosis by the soluble guanylyl cyclase/cGMP pathway in human ovarian cancer cells. Oncogene, 25, 2203-2212 https://doi.org/10.1038/sj.onc.1209251
  23. Genestier, L., Paillot, R., Quemeneur, L., Izeradjene, K. and Revillard, J.P. (2000). Mechanisms of action of methotrexate. Immunopharmacology, 47, 247-257 https://doi.org/10.1016/S0162-3109(00)00189-2
  24. Henley, D.V. and Korach, K.S. (2006). Endocrine-disrupting chemicals use distinct mechanisms of action to modulate endocrine system function. Endocrinology, 147, 25-32 https://doi.org/10.1210/en.2005-1117
  25. Kang, H.J., Song, M.R., Lee, S.K., Shin, E.C., Choi, Y.H., Kim, S.J., Lee, J.W. and Lee, M.O. (2000). Retinoic acid and its receptors repress the expression and transactivation functions of Nur77: a possible mechanism for the inhibition of apoptosis by retinoic acid. Exp. Cell Res., 256, 545-554 https://doi.org/10.1006/excr.2000.4832
  26. Kendig, D.M. and Tarloff, J.B. (2007). Inactivation of lactate dehydrogenase by several chemicals: implications for in vitro toxicology studies. Toxicol. In Vitro, 21, 125-132 https://doi.org/10.1016/j.tiv.2006.08.004
  27. Klaunig, J.E., Xu, Y., Isenberg, J.S., Bachowski, S., Kolaja, K.L., Jiang, J., Stevenson. D.E. and Walborg, E.F Jr. (1998). The role of oxidative stress in chemical carcinogenesis. Environ. Health Perspect., 1, 289-295
  28. Knasmuller, S., Parzefall, W., Helma, C., Kassie, F., Ecker, S. and Schulte-Hermann, R. (1998). Toxic effects of griseofulvin: disease models, mechanisms, and risk assessment. Crit. Rev. Toxicol., 27, 495-537 https://doi.org/10.3109/10408449709078444
  29. Korge, P. and Weiss, J.N. (1999). Thapsigargin directly induces the mitochondrial permeability transition. Eur. J. Biochem., 265, 273-280 https://doi.org/10.1046/j.1432-1327.1999.00724.x
  30. Lee, S.K., Kim, H.J., Kim, J.W. and Lee, J.W. (1999). Steroid receptor coactivator-1 and its family members differentially regulate transactivation by the tumor suppressor protein p53. Mol. Endocrinol., 13, 1924-1933 https://doi.org/10.1210/me.13.11.1924
  31. Nakadate, T. (1989). The mechanism of skin tumor promotion caused by phorbol esters: possible involvement of arachidonic acid cascade/lipoxygenase, protein kinase C and calcium/calmodulin systems. Jpn. J. Pharmacol., 49, 1-9 https://doi.org/10.1254/jjp.49.1
  32. Nishizuka, Y. (1984). The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature, 308, 693-698 https://doi.org/10.1038/308693a0
  33. Schmidt, K.N., Traenckner, E.B., Meier, B. and Baeuerle, P.A. (1995). Induction of oxidative stress by okadaic acid is required for activation of transcription factor NF-kappa B. J. Biol. Chem., 270, 27136-27142 https://doi.org/10.1074/jbc.270.45.27136
  34. Seifried, H.E., McDonald, S.S., Anderson, D.E., Greenwald, P. and Milner, J.A. (2003). The antioxidant conundrum in cancer. Cancer Res., 63, 4295-4298
  35. Seth, P.K. (1982). Hepatic effects of phthalate esters. Environ. Health Perspect., 45, 27-34 https://doi.org/10.2307/3429380
  36. Tennant, R.W., Margolin, B.H., Shelby, M.D., Zeiger, E., Haseman, J.K., Spalding, J., Caspary, W., Resnick, M., Stasiewicz, S. and Anderson, B. (1987). Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. Science, 236, 933-941 https://doi.org/10.1126/science.3554512
  37. Trosko, J.E. (2001). Commentary: is the concept of 'tumor promotion' a useful paradigm? Mol. Carcinog., 30, 131- 137 https://doi.org/10.1002/mc.1021
  38. Verma, A.K., Hsieh, J.T. and Pong, R.C. (1988). Mechanisms involved in ornithine decarboxylase induction by 12-O-tetradecanoylphorbol- 13-acetate, a potent mouse skin tumor promoter and an activator of protein kinase C. Adv. Exp. Med. Biol., 1250, 273-290
  39. Wang, X.D. and Russell, R.M. (1999). Procarcinogenic and anticarcinogenic effects of beta-carotene. Nutr. Rev., 57, 263-272
  40. Yamasaki, H. (1990). Gap junctional intercellular communication and carcinogenesis. Carcinogenesis, 11, 1051-105 https://doi.org/10.1093/carcin/11.7.1051