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Differential Expression and Stability of Endogenous Nuclear Factor E2-related Factor 2 (Nrf2) by Natural Chemopreventive Compounds in HepG2 Human Hepatoma Cells

  • Jeong, Woo-Sik (Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey) ;
  • Keum, Young-Sam (Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey) ;
  • Chen, Chi (Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey) ;
  • Jain, Mohit R. (Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey) ;
  • Shen, Guoxiang (Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey) ;
  • Kim, Jung-Hwan (Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey) ;
  • Li, Wenge (Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey) ;
  • Kong, Ah-Ng Tony (Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey)
  • Published : 2005.03.31
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Abstract

Nuclear factor-E2-related factor 2 (Nrf2) is known as a key regulator of ARE-mediated gene expression and the induction of Phase II detoxifying enzymes and antioxidant enzymes, which is also a common property of many chemopreventive agents. In the present study, we investigated the regulatory role of different chemopreventive agents including sulforaphane (SUL), allyl isothiocyanate (AITC), indole-3-carbinol (I3C), and parthenolide (PTL), in the expression and degradation of Nrf2 and the induction of the antioxidant enzyme HO-1. SUL strongly induced Nrf2 protein expression and ARE-mediated transcription activation, retarded degradation of Nrf2 through inhibiting Keap1, and thereby activating the transcriptional expression of HO-1. AITC was also a potent inducer of Nrf2 protein expression, ARE-reporter gene and HO-1 but had little effect on delaying the degradation of Nrf2 protein. Although PTL and I3C could induce ARE reporter gene expression and Nrf2 to some extent, they were not as potent as SUL and AITC. However, PTL dramatically induced the HO-1 expression, which was comparable to SUL, while I3C had no effect. In addition, when treated with SUL and PTL, inhibition of proteasome by MG132 did not cause additional accumulation of Nrf2, suggesting the involvement of other degradation mechanism(s) in the presence of these compounds such as SUL and PTL. In summary, the results of our current study indicated that different chemopreventive compounds have different regulatory properties on the accumulation and degradation of Nrf2 as well as the induction of cellular antioxidant enzyme HO-1.

Keywords

References

  1. Alam, J., Wicks, C., Stewart, D., Gong, P., Touchard, C., Otterbein, S., Choi, A. M., Burow, M. E. and Tou, J. (2000) Mechanism of heme oxygenase-1 gene activation by cadmium in MCF-7 mammary epithelial cells. Role of p38 kinase and Nrf2 transcription factor. J. Biol. Chem. 275, 27694-27702
  2. Alcaraz, M. J., Fernandez, P. and Guillen, M. I. (2003) Antiinflammatory actions of the heme oxygenase-1 pathway. Curr. Pharm. Des. 9, 2541-2551 https://doi.org/10.2174/1381612033453749
  3. Balogun, E., Hoque, M., Gong, P., Killeen, E., Green, C. J., Foresti, R., Alam, J. and Motterlini, R. (2003) Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem. J. 371, 887- 895 https://doi.org/10.1042/BJ20021619
  4. Chen, C., Yu, R., Owuor, E. D. and Kong, A. N. (2000) Activation of antioxidant-response element (ARE), mitogenactivated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death. Arch. Pharm. Res. 23, 605-612 https://doi.org/10.1007/BF02975249
  5. Cullinan, S. B., Zhang, D., Hannink, M., Arvisais, E., Kaufman, R. J. and Diehl, J. A. (2003) Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol. Cell. Biol. 23, 7198-7209 https://doi.org/10.1128/MCB.23.20.7198-7209.2003
  6. Dhakshinamoorthy, S. and Jaiswal, A. K. (2001) Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. Oncogene 20, 3906- 3917 https://doi.org/10.1038/sj.onc.1204506
  7. Durante, W. (2003) Heme oxygenase-1 in growth control and its clinical application to vascular disease. J. Cell. Physiol. 195, 373-382 https://doi.org/10.1002/jcp.10274
  8. Fahey, J. W., Haristoy, X., Dolan, P. M., Kensler, T. W., Scholtus, I., Stephenson, K. K., Talalay, P. and Lozniewski, A. (2002) Sulforaphane inhibits extracellular, intracellular, and antibioticresistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc. Natl. Acad. Sci. USA 99, 7610-7615. https://doi.org/10.1073/pnas.112203099
  9. Favreau, L. V. and Pickett, C. B. (1991) Transcriptional regulation of the rat NAD(P)H:quinone reductase gene. Identification of regulatory elements controlling basal level expression and inducible expression by planar aromatic compounds and phenolic antioxidants. J. Biol. Chem. 266, 4556-4561
  10. Haridas, V., Hanausek, M., Nishimura, G., Soehnge, H., Gaikwad, A., Narog, M., Spears, E., Zoltaszek, R., Walaszek, Z. and Gutterman, J. U. (2004) Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery. J. Clin. Invest. 113, 65-73 https://doi.org/10.1172/JCI200418699
  11. Huang, H. C., Nguyen, T. and Pickett, C. B. (2000) Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. Proc. Natl. Acad. Sci. USA 97, 12475-12480 https://doi.org/10.1073/pnas.220418997
  12. Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., Yamamoto, M. and Nabeshima, Y. (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236, 313-322 https://doi.org/10.1006/bbrc.1997.6943
  13. Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D. and Yamamoto, M. (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes. Dev. 13, 76-86 https://doi.org/10.1101/gad.13.1.76
  14. Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., O'Connor, T. and Yamamoto, M. (2003) Keap1 regulates both cytoplasmicnuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells 8, 379-391 https://doi.org/10.1046/j.1365-2443.2003.00640.x
  15. Jaiswal, A. K. (2000) Regulation of genes encoding NAD(P)H:quinone oxidoreductases. Free Radic. Biol. Med. 29, 254-262 https://doi.org/10.1016/S0891-5849(00)00306-3
  16. Jaiswal, A. K. (2004) Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic. Biol. Med. 36, 1199- 207 https://doi.org/10.1016/j.freeradbiomed.2004.02.074
  17. Keum, Y. S., Owuor, E. D., Kim, B. R., Hu, R. and Kong, A. N. (2003) Involvement of Nrf2 and JNK1 in the activation of antioxidant responsive element (ARE) by chemopreventive agent phenethyl isothiocyanate (PEITC). Pharm. Res. 20, 1351- 1356 https://doi.org/10.1023/A:1025737622815
  18. Kim, B. R., Hu, R., Keum, Y. S., Hebbar, V., Shen, G., Nair, S. S. and Kong, A. N. (2003) Effects of glutathione on antioxidant response element-mediated gene expression and apoptosis elicited by sulforaphane. Cancer Res. 63, 7520-7525
  19. Kong, A. N., Yu, R., Hebbar, V., Chen, C., Owuor, E., Hu, R., Ee, R. and Mandlekar, S. (2001) Signal transduction events elicited by cancer prevention compounds. Mutat. Res. 480, 231-241 https://doi.org/10.1016/S0027-5107(01)00182-8
  20. Kwak, M. K., Itoh, K., Yamamoto, M. and Kensler, T. W. (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response elementlike sequences in the nrf2 promoter. Mol. Cell. Biol. 22, 2883- 2892 https://doi.org/10.1128/MCB.22.9.2883-2892.2002
  21. McMahon, M., Itoh, K., Yamamoto, M. and Hayes, J. D. (2003) Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J. Biol. Chem. 278, 21592-21600 https://doi.org/10.1074/jbc.M300931200
  22. Morimitsu, Y., Nakagawa, Y., Hayashi, K., Fujii, H., Kumagai, T., Nakamura, Y., Osawa, T., Horio, F., Itoh, K., Iida, K., Yamamoto, M. and Uchida, K. (2002) A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway. J. Biol. Chem. 277, 3456-3463 https://doi.org/10.1074/jbc.M110244200
  23. Nakaso, K., Yano, H., Fukuhara, Y., Takeshima, T., Wada-Isoe, K. and Nakashima, K. (2003) PI3K is a key molecule in the Nrf2- mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett 546, 181-184 https://doi.org/10.1016/S0014-5793(03)00517-9
  24. Nguyen, T., Sherratt, P. J., Huang, H. C., Yang, C. S. and Pickett, C. B. (2003) Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26 S proteasome. J. Biol. Chem. 278, 4536-4541 https://doi.org/10.1074/jbc.M207293200
  25. Primiano, T., Sutter, T. R. and Kensler, T. W. (1997) Antioxidantinducible genes. Adv. Pharmacol. 38, 293-328 https://doi.org/10.1016/S1054-3589(08)60989-8
  26. Ramos-Gomez, M., Kwak, M. K., Dolan, P. M., Itoh, K., Yamamoto, M., Talalay, P. and Kensler, T. W. (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factordeficient mice. Proc. Natl. Acad. Sci. USA 98, 3410-3415 https://doi.org/10.1073/pnas.051618798
  27. Rushmore, T. H., Morton, M. R. and Pickett, C. B. (1991) The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J. Biol. Chem. 266, 11632-11639
  28. Shen, G., Hebbar, V., Nair, S., Xu, C., Li, W., Lin, W., Keum, Y. S., Han, J., Gallo, M. A. and Kong, A. N. (2004) Regulation of Nrf2 transactivation domain activity: the differential effects of mitogen-activated protein kinase cascades and synergistic stimulatory effect of raf and creb-binding protein. J. Biol. Chem. 279, 23052-23060 https://doi.org/10.1074/jbc.M401368200
  29. Stewart, D., Killeen, E., Naquin, R., Alam, S. and Alam, J. (2003) Degradation of transcription factor Nrf2 via the ubiquitinproteasome pathway and stabilization by cadmium. J. Biol. Chem. 278, 2396-2402 https://doi.org/10.1074/jbc.M209195200
  30. Talalay, P. and Fahey, J. W. (2001) Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism. J. Nutr. 131, 3027-3033
  31. Venugopal, R. and Jaiswal, A. K. (1996) Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc. Natl. Acad. Sci. USA 93, 14960- 14965 https://doi.org/10.1073/pnas.93.25.14960
  32. Wen, J., You, K. R., Lee, S. Y., Song, C. H. and Kim, D. G. (2002) Oxidative stress-mediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide. J. Biol. Chem. 277, 38954-38964 https://doi.org/10.1074/jbc.M203842200
  33. Wu, L. and Juurlink, B. H. (2001) The impaired glutathione system and its up-regulation by sulforaphane in vascular smooth muscle cells from spontaneously hypertensive rats. J. Hypertens. 19, 1819-1825 https://doi.org/10.1097/00004872-200110000-00016
  34. Yang, C. S., Maliakal, P. and Meng, X. (2002) Inhibition of carcinogenesis by tea. Annu. Rev. Pharmacol. Toxicol. 42, 25- 54 https://doi.org/10.1146/annurev.pharmtox.42.082101.154309
  35. Yu, R., Chen, C., Mo, Y. Y., Hebbar, V., Owuor, E. D., Tan, T. H. and Kong, A. N. (2000) Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism. J. Biol. Chem. 275, 39907-39913 https://doi.org/10.1074/jbc.M004037200
  36. Yu, R., Lei, W., Mandlekar, S., Weber, M. J., Der, C. J., Wu, J. and Kong, A. T. (1999) Role of a mitogen-activated protein kinase pathway in the induction of phase II detoxifying enzymes by chemicals. J. Biol. Chem. 274, 27545-27552 https://doi.org/10.1074/jbc.274.39.27545
  37. Zhang, D. D. and Hannink, M. (2003) Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol. Cell. Biol. 23, 8137-8151 https://doi.org/10.1128/MCB.23.22.8137-8151.2003
  38. Zhang, S., Ong, C. N. and Shen, H. M. (2004) Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Lett. 208, 143-153 https://doi.org/10.1016/j.canlet.2003.11.028

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