Up-regulation of Aldo-keto Reductase 1C3 Expression in Sulforaphane-treated MCF-7 Breast Cancer Cells

  • Lee, Sang-Han (Department of Biochemistry, College of Medicine, Soonchunhyang University)
  • Published : 2008.10.31

Abstract

The chemopreventive activity of sulforaphane (SFN) occurs through its inhibition of carcinogen-activating enzymes and its induction of detoxification enzymes. However, the exact mechanisms by which SFN exerts its anti-carcinogenic effects are not fully understood. Therefore, the mechanisms underlying the cytoprotective effects of SFN were examined in MCF-7 breast cancer cells. Exposure of cells to SFN (10 ${\mu}M$) induced a transcriptional change in the AKR1C3 gene, which is one of aldo-keto reductases (AKRs) family that is associated with detoxification and antioxidant response. Further analysis revealed that SFN elicited a dose- and time-dependent increase in the expression of both the NRF2 and AKR1C3 proteins. Moreover, this up-regulation of AKR1C3 was inhibited by pretreatment with antioxidant, N-acetyl-L-cysteine (NAC), which suggests that the up-regulation of AKR1C3 expression induced by SFN involves reactive oxygen species (ROS) signaling. Furthermore, pretreatment of cells with LY294002, a pharmacologic inhibitor of phosphatidylinositol 3-kinase (PI3K), suppressed the SFN-augmented Nrf2 activation and AKR1C3 expression; however, inhibition of PKC or MEK1/2 signaling with $G\ddot{o}6976$ or PD98059, respectively, did not alter SFN-induced AKR1C3 expression. Collectively, these data suggest that SFN can modulate the expression of the AKR1C3 in MCF-7 cells by activation of PI3K via the generation of ROS.

Keywords

References

  1. Kushad MM, Brown AF, Kurilich AC, Juvik JA, Klein BP, Wailing MA, Jeffery EH. Variation of glucosinolates in vegetable crops of Brassica oleracea. J. Agr. Food Chem. 47: 1541-1548 (1999) https://doi.org/10.1021/jf980985s
  2. Myzak MC, Dashwood WM, Orner GA, Ho E, Dashwood RH. Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apc-minus mice. FASEB J. 20: 506-508 (2006) https://doi.org/10.1096/fj.05-4785fje
  3. Chuang LT, Moqattash ST, Gretz HF, Nezhat F, Rahaman J, Chiao JW. Sulforaphane induces growth arrest and apoptosis in human ovarian cancer cells. Acta Obstet. Gyn. Sca. 16: 1-6 (2007)
  4. Matsui TA, Murata H, Sakabe T, Sowa Y, Horie N, Nakanishi R, Sakai T, Kubo T. Sulforaphane induces cell cycle arrest and apoptosis in murine osteosarcoma cells in vitro and inhibits tumor growth in vivo. Oncol. Rep. 18: 1263-1268 (2007)
  5. Conaway CC, Wang CX, Pittman B, Yang YM, Schwartz JE, Tian D, McIntee EJ, Hecht SS, Chung FL. Phenethylisothiocyanate and sulforaphane and their N-acetylcysteine conjugates inhibit malignant progression of lung adenomas induced by tobacco carcinogens in A/J mice. Cancer Res. 65: 8548-8557 (2005) https://doi.org/10.1158/0008-5472.CAN-05-0237
  6. Lee SB, Lee JY, Song DG, Pan CH, Nho CW, Kim MC, Lee EH, Jung SH, Kim HS, Kim YS, Um BH. Cancer chemopreventive effects Korean seaweed extracts. Food Sci. Biotechnol. 17: 613-622 (2008)
  7. Zhang Y, Talalay P, Cho CG, Posner GH. A major inducer of anticarcinogenic protective enzymes from broccoli: Isolation and elucidation of structure. P. Natl. Acad. Sci. USA 89: 2399-2403 (1992)
  8. Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P, Kensler TW. Sensitivity to carcinogenesis is increased and chemopreventive efficacy of enzyme inducers is lost in Nrf2 transcription factor-deficient mice. P. Natl. Acad. Sci. USA 98: 3410-3415 (2001)
  9. Verhoeven DT, Goldbohm RA, van Poppel G, Verhagen H, van den Brandt PA. Epidemiological studies on brassica vegetables and cancer risk. Cancer Epidem. Biomar. 5: 733-748 (1996)
  10. Cohen JH, Kristal AR, Stanford JL. Fruit and vegetable intakes and prostate cancer risk. J. Natl. Cancer Inst. 92: 61-68 (2000) https://doi.org/10.1093/jnci/92.1.61
  11. Ambrosone CB, McCann SE, Freudenheim JL, Marshall JR, Zhang Y, Shields PG. Breast cancer risk in premenopausal women is inversely associated with consumption of broccoli, a source of isothiocyanates, but is not modified by GST genotype. J. Nutr. 134: 1134-1138 (2004) https://doi.org/10.1093/jn/134.5.1134
  12. Lee SH, Shiao YH, Kasprzak KS. Nonradioactive mRNA differential display in polyacrylamide mini-gels. Res. Co. Mol. Path. 106: 108-114 (1999)
  13. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap 1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Gene Dev. 13: 76-86 (1999) https://doi.org/10.1101/gad.13.1.76
  14. Jin Y, Penning TM. Aldo-keto reductases and bioactivation/detoxication. Annu. Rev. Pharmacol. 47: 263-292 (2007) https://doi.org/10.1146/annurev.pharmtox.47.120505.105337
  15. Ellis EM. Reactive carbonyls and oxidative stress: Potential for therapeutic intervention. Pharmacol. Therapeut. 115: 13-24 (2007) https://doi.org/10.1016/j.pharmthera.2007.03.015
  16. Penning TM. Aldo-keto reductases and formation of polycyclic aromatic hydrocarbon O-quinones. Methods Enzymol. 378: 31-67 (2004) https://doi.org/10.1016/S0076-6879(04)78003-9
  17. Hyndman D, Bauman DR, Heredia VV, Penning TM. The aldo-keto reductase superfamily homepage. Chem. Biol. Interact. 143-144: 499-525 (2003)
  18. Burczynski ME, Lin HK, Penning TM. Isoform-specific induction of a human aldo-keto reductase by polycyclic aromatic hydrocarbons (PAHs), electrophiles, and oxidative stress: Implications for the alternative pathway of PAH activation catalyzed by human dihydrodiol dehydrogenase. Cancer Res. 59: 607-614 (1999)
  19. Wang XJ, Hayes JD, Wolf CR. Generation of a stable antioxidant response element-driven reporter gene cell line and its use to show redox-dependent activation of nrf2 by cancer chemotherapeutic agents. Cancer Res. 66: 10983-10994 (2006) https://doi.org/10.1158/0008-5472.CAN-06-2298
  20. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. 47: 89-116 (2007) https://doi.org/10.1146/annurev.pharmtox.46.120604.141046
  21. Singh SV, Srivastava SK, Choi S, Lew KL, Antosiewicz J, Xiao D, Zeng Y, Watkins SC, Johnson CS, Trump DL, Lee YJ, Xiao H, Herman-Antosiewicz A. Sulforaphane-induced cell death in human prostate cancer cells is initiated by reactive oxygen species. J. Biol. Chem. 280: 19911-19924 (2005) https://doi.org/10.1074/jbc.M412443200
  22. Suh YA, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK, Lambeth JD. Cell transformation by the superoxide-generating oxidase Mox1. Nature 401: 79-82 (1999) https://doi.org/10.1038/43459
  23. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120: 649-661 (2005) https://doi.org/10.1016/j.cell.2004.12.041
  24. Chen KC, Zhou Y, Zhang W, Lou MF. Control of PDGF-induced reactive oxygen species (ROS) generation and signal transduction in human lens epithelial cells. Mol. Vis. 13: 374-387 (2007)
  25. Biswas S, Gupta MK, Chattopadhyay D, Mukhopadhyay CK. Insulin-induced activation of hypoxia-inducible factor-1 requires generation of reactive oxygen species by NADPH oxidase. Am. J. Physiol. -Heart C. 292: H758-H766 (2007) https://doi.org/10.1152/ajpheart.00718.2006
  26. Harrison EM, McNally SJ, Devey L, Garden OJ, Ross JA, Wigmore SJ. Insulin induces heme oxygenase-1 through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in renal cells. FEBS J. 273: 2345-2356 (2006) https://doi.org/10.1111/j.1742-4658.2006.05224.x
  27. Jakubikova J, Sedlak J, Mithen R, Bao Y. Role of PI3K/Akt and MEK/ERK signaling pathways in sulforaphane- and erucin-induced phase II enzymes and MRP2 transcription, G2/M arrest, and cell death in Caco-2 cells. Biochem. Pharmacol. 69: 1543-1552 (2005) https://doi.org/10.1016/j.bcp.2005.03.015
  28. Yu R, Chen C, Mo YY, Hebbar V, Owuor ED, Tan TH, Kong AN. 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 (2000) https://doi.org/10.1074/jbc.M004037200
  29. Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat. Rev. Cancer 3: 768-780 (2003) https://doi.org/10.1038/nrc1189
  30. Gharavi N, Haggarty S, El-Kadi AO. Chemoprotective and carcinogenic effects of tert-butylhydroquinone and its metabolites. Curr. Drug Metab. 8: 1-7 (2007)
  31. Nakaso K, Yano H, Fukuhara Y, Takeshima T, Wada-Isoe K, Nakashima K. PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett. 546: 181-184 (2003) https://doi.org/10.1016/S0014-5793(03)00517-9