臺灣博碩士論文加值系統

近年來癌症一直位居十大死因之第一位，大部分癌症的發生與環境或職業中的致癌因子有關。其中膀胱癌與存在於香煙、油煙、偶氮染料之聯苯胺類化學成分之暴露有密切之相關性。然而聯苯胺類化學成分誘導膀胱癌發生的分子機制，至今仍未非常清楚。許多相關的文獻指出環氧酵素二型(Cyclooxygenase-2, COX-2)的過度表現與癌症的發生過程具有關聯性。本研究中我們將分析二氨基聯苯(2-Aminobiphenyl, 2-ABP)是否會誘導細胞中Cyclooxygenase-2表現。並且更進一步的探討在人類膀胱癌細胞TSGH-8301中，聯苯胺化合物誘導COX-2表現之訊息傳遞路徑。本實驗室研究結果顯示隨著二氨基聯苯處理時間或劑量的增加，皆可誘導細胞內COX-2表現增加。2-ABP同時可促進ROS及Mitogen-activated protein kinase中ERK和JNK的活化以及轉錄因子c-Jun表現增加和ATF-2磷酸化。此外，當細胞同時處理了ERK (U0126)及JNK (SP600125)的抑制劑後，可將2-ABP誘導的COX-2、c-Jun表現及ATF-2磷酸化抑制下來；ROS的清除劑；N-acetyl cysteine (NAC)同樣也可以抑制2-ABP所誘導的COX-2表現和c-Jun、ATF-2磷酸化。除此之外，NADPH oxidase抑制劑 Apocynin對於2-ABP所誘導的COX-2表現和c-Jun、ATF-2磷酸化有顯著的抑制作用。同時2-胺基聯苯刺激下也會誘導細胞中NADPH oxidase subunit p22的表現。以上結果顯示2-ABP可經由NADPH oxidase調控細胞中ROS產生並促進JNK以及ERK活化，並經由轉錄因子c-Jun 和ATF-2，進而誘導COX-2表現增加。

Cancer is the leading cause of death in recent year. Environmental or occupational carcinogen exposure is closely related to cancer occurrences. It has been reported that overexposure of biphenyl amine compounds contained in smoke and azo-dyes is related to bladder cancer occurrence. However, the molecular mechanisms of biphenyl amine compounds-induced bladder cancer are still unclear. Many studies have demonstrated that overexpression of cyclooxygenase-2 (COX-2) in neoplastic lesions is associated with carcinogenesis. Whether the biphenyl amine compounds could regulate the expression of COX-2 was investigated in this study. The signaling pathways of biphenyl amine compound-induced COX-2 expression in human bladder cancer cell lines TSGH-8301 cells were further examined. We found that 2-Aminobiphenyl (2-ABP) could induce COX-2 expression in a dose- and time-dependent manner. The reactive oxygen species production (ROS) production, phosphorylation of mitogen-activated protein kinase, ERK and JNK, and activation of transcription factor c-Jun, ATF-2 were enhanced by 2-ABP treatment. Moreover, 2-ABP induced COX-2 expression, ERK/JNK and c-Jun, ATF-2 phosphorylation were significantly inhibited by JNK inhibitor (SP600125) and ERK1/2 inhibitor (U0126). The ROS scavenger, N-acetyl cysteine (NAC), also could attenuate 2-ABP-induced COX-2 expression and c-Jun, ATF-2 phosphorylation. Furthermore, we found that NADPH oxidase inhibitor (apocynin) also has the same inhibitory effects on 2-ABP-induced COX-2 expression and c-Jun, ATF-2 phosphorylation. Stimulation of 2-ABP was also found to induce the expression of NADPH oxidase subunit p22. These results indicated that 2-ABP induces COX-2 expression mediated through NADPH oxidase stimulated ROS production and JNK/ERK activation, which is regulated by transcription factors c-Jun and ATF-2.

誌謝 ................................................................................................................ I
中文摘要 ...................................................................................................... II
英文摘要 ..................................................................................................... III
目錄 ............................................................................................................. IV
圖目錄 ....................................................................................................... VII
壹、 前言 ..................................................................................................... 1
1.1 膀胱癌 (Bladder cancer) ....................................................................... 1
1.2 環氧酵素 (Cyclooxygenase) ................................................................. 3
1.3 環氧酵素 (Cyclooxygenase)特性 ......................................................... 4
1.4 2-胺基聯苯 (2-Aminobiphenyl) ............................................................ 7 1.5 絲裂原活化蛋白激酶路徑 (Mitogen-activated protein kinase 0pathway） ............................................................................................... 8
1.6 轉錄因子 (Transcription factor) ........................................................... 9 1.6.1 Activating protein-1 (AP-1) ........................................................... 9 1.6.2 Nuclear factor-kappa B (NF-κB) ................................................. 11
1.7 自由基 (Reactive oxygen species, ROS)及NADPH氧化酶0(Nicotinamide adenine dinucleotide phosphate-oxidase, NADPH 0oxidase) ................................................................................................. 12
1.8 研究目的 (Specific aims of this study) .............................................. 14
貳、 材料與方法 ....................................................................................... 16
2.1 實驗材料 .............................................................................................. 16
2.2 實驗方法 .............................................................................................. 20
2.2.1 冷凍細胞的活化 ........................................................................ 20
2.2.2 細胞的冷凍保存 ........................................................................ 21
2.2.3 細胞培養 ..................................................................................... 21
2.2.4 細胞數計算................................................................................. 22
2.2.5 蛋白質濃度測定 ........................................................................ 22
2.2.6 MTT assay ................................................................................... 24
2.2.7 DCFH-DA assay .......................................................................... 24
2.2.8 西方點墨法 (Western blot) ....................................................... 25
2.2.9 Western Blot Stripping ................................................................ 29
2.2.10 細胞溶解液(cell lysate)之製備 ................................................ 30
2.2.11 RNA extraction .......................................................................... 31
2.2.12 RT PCR ...................................................................................... 31
2.2.13 抑制劑之處理 .......................................................................... 34
參、 結果 ................................................................................................... 35
3.1 2-胺基聯苯對於TSGH-8301 膀胱癌細胞株的細胞存活率影響 .... 35
3.2 2-胺基聯苯誘導TSGH-8301 膀胱癌細胞株中環氧酵素二型的表現 ................................................................................................................ 35
3.3 2-胺基聯苯會誘導TSGH-8301膀胱癌細胞株中ROS的產生........ 36
3.4 2-胺基聯苯可經由NADPH oxidase/ROS誘導COX-2表現增加 ... 36
3.5 2-胺基聯苯誘導MAPK路徑及下游轉錄因子的活化 ...................... 37
3.6 2-胺基聯苯可經由活化MAPK路徑誘導COX-2表現增加 ............ 39
3.7 2-胺基聯苯經由NADPH oxidase/ROS 所誘導的環氧酵素二型表現是經由MAPK pathway所活化 ............................................................ 40
3.8 2-胺基聯苯可藉由活化轉錄因子c-Jun及ATF-2誘導環氧酵素二型的表現 .................................................................................................... 41
肆、 討論 ................................................................................................... 43
4.1 2-胺基聯苯刺激下會誘導TSGH-8301膀胱癌細胞中環氧酵素二型的大量表現 ............................................................................................ 43
4.2 2-胺基聯苯誘導刺激下會經由NADPH/ROS誘導TSGH-8301膀胱癌細胞株中環氧酵素二型的表現 ........................................................ 44
4.3 2-胺基聯苯誘導TSGH-8301膀胱癌細胞株中環氧酵素二型表現是由NADPH/ROS活化MAPK訊息傳遞路徑所調控 ......................... 46
4.4 2-胺基聯苯所誘導的環氧酵素二型表現是經由轉錄因子c-Jun及ATF-2所調控，並且是經由ERK及JNK訊息傳遞路徑誘導 ........ 48
伍、 結論 ................................................................................................... 51
陸、 參考文獻 ........................................................................................... 53

柒、 附錄 ................................................................................................... 89
7.1 附錄一 Two isoforms of COX: COX 1 and COX 2 ........................... 89
7.2 附錄二 COX2 is upregulated in several invasive tumour types ......... 90
7.3 附錄三 Signalling pathways involved in the regulation of 0000000COX-2expression ..................................................................... 91
7.4 附錄四 Mechanisms of NADPH oxidase inhibition .......................... 92
7.5 附錄五 The action principle of fluorescent dye DCFH-DA............... 93
7.6 附錄六 Chemical structure of 2-aminobiphenyl................................. 94
7.7 附錄七 Antibody dilution buffer and ratio ......................................... 95

圖目錄
Fig.1. Effect of 2-Aminobiphenyl on TSGH8301 cell viability and COX-2 expression. ........................................................................ 65
Fig. 2. 2-Aminobiphenyl induced COX-2 gene expression in a dose-dependent manner. ................................................................ 66
Fig. 3. 2-Aminobiphenyl induced COX-2 gene expression in a time-dependent manner .. .............................................................. 67
Fig. 4. 2-Aminobiphenyl induces ROS production in a time and dose-dependent manner.. ............................................................... 68
Fig. 5. Suppression of ROS production by pharmacological inhibitors and also attenuates COX-2 induction.. ......................................... 69
Fig. 6. ROS is a fundamental element during 2-ABP-induced COX-2 expression in TSGH-8301 cell line.. ............................................. 71
Fig. 7. Effect of NADPH oxidase inhibitor DPI (Diphenyleneiodonium chloride) on 2-aminobiphenyl-induced COX-2 expression.. ........ 72
Fig. 8. Time-dependent expression of p22-phox expression in TSGH-8301 cell line after exposure to 2-ABP.. ........................... 73
Fig. 9. Activation of ERK1/2 and JNK by 2-aminobiphenyl in a time-dependent manner. ................................................................ 74
Fig. 10. Induction of transcription factor c-Jun and ATF2 is required for 2-ABP-induced COX-2 expression. ........................................... 75
Fig. 11. Involvement of MAPK pathways in 2-ABP-induced COX-2 expression. ................................................................................... 77
Fig. 12. Effect of NF-κB inhibitor BAY11-7082 on 2-aminobiphenyl-induced COX-2 expression.. .......................... 78
Fig.13. 2-ABP-induced COX-2 expression is mediated through NADPH oxidase-derived ROS dependent MAPK activation.. ................. 80
Fig. 14. Suppression of ROS production by pharmacological inhibitors and also attenuates COX-2 induction. ........................................ 81
VIII
Fig. 15. Induction of transcription factor c-Jun and ATF2, which is mediated through ROS-dependent ERK and JNK cascades, is required for 2-ABP-induced COX-2 expression. ....................... 84
Fig. 16. Effect of AP-1 inhibitor on 2-aminobiphenyl–induced COX-2 expression. ................................................................................... 85
Fig. 17. Effect of 2-aminobiphenyl on COX-2 expression with COX-2 active inhibitor (NS398) at 24 h. ................................................ 86
Fig. 18. Effect of aromatic amines chemical on COX-2 expression in TSGH-8301 cell line. .................................................................. 87
Fig. 19. Signaling transduction pathways involving in 2-aminobiphenyl regulating cyclooxygenase-2 expression in TSGH-8301 bladder cancer cell line. ........................................................................... 88

1. Sexton, W.J., L.R. Wiegand, J.J. Correa, C. Politis, S.I. Dickinson, and L.C. Kang, Bladder cancer: a review of non-muscle invasive disease. Cancer Control, 2010. 17(4): p. 256-68.
2. Youssef, R.F. and Y. Lotan, Predictors of outcome of non-muscle-invasive and muscle-invasive bladder cancer. ScientificWorldJournal, 2011. 11: p. 369-81.
3. Kanitz, M.H., S. Swaminathan, and R.E. Savage, Jr., Two-dimensional electrophoretic protein profile analysis following exposure of human uroepithelial cells to occupational bladder carcinogens. Cancer Lett, 2004. 205(2): p. 121-31.
4. Cotran, R.S., V. Kumar, and S.L. Robbins, The lower urinary tract. In Robbins Pathologic basis of disease, 5th ed.(Frederick J. Schoen, ed.). W. B. Saunders Company, 1994: p. pp. 991-1005.
5. Jensen, O.M., J. Wahrendorf, M. Blettner, J.B. Knudsen, and B.L. Sorensen, The Copenhagen case-control study of bladder cancer: role of smoking in invasive and non-invasive bladder tumours. J Epidemiol Community Health, 1987. 41(1): p. 30-6.
6. Quirk, J.T., Q. Li, N. Natarajan, C.J. Mettlin, and K.M. Cummings, Cigarette smoking and the risk of bladder cancer in men and women. Tob Induc Dis, 2004. 2(3): p. 141-4.
7. Gago-Dominguez, M., D.A. Bell, M.A. Watson, J.M. Yuan, J.E. Castelao, D.W. Hein, K.K. Chan, G.A. Coetzee, R.K. Ross, and M.C. Yu, Permanent hair dyes and bladder cancer: risk modification by cytochrome P4501A2 and N-acetyltransferases 1 and 2. Carcinogenesis, 2003. 24(3): p. 483-9.
8. Dannenberg, A.J., N.K. Altorki, J.O. Boyle, C. Dang, L.R. Howe, B.B. Weksler, and K. Subbaramaiah, Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer. Lancet Oncol, 2001. 2(9): p. 544-51.
9. Tsatsanis, C., A. Androulidaki, M. Venihaki, and A. Margioris, Signalling networks regulating cyclooxygenase-2. The International Journal of Biochemistry & Cell Biology, 2006. 38(10): p. 1654-1661.
10. Deng, W.G., Y. Zhu, and K.K. Wu, Role of p300 and PCAF in regulating cyclooxygenase-2 promoter activation by inflammatory mediators. Blood, 2004. 103(6): p. 2135-42.
54
11. Vane, J.R., The history of inhibitors of angiotensin converting enzyme. J Physiol Pharmacol, 1999. 50(4): p. 489-98.
12. Hsieh, H.L., H.H. Wang, C.Y. Wu, M.J. Jou, M.H. Yen, P. Parker, and C.M. Yang, BK-induced COX-2 expression via PKC-delta-dependent activation of p42/p44 MAPK and NF-kappaB in astrocytes. Cell Signal, 2007. 19(2): p. 330-40.
13. Gasparini, G., R. Longo, R. Sarmiento, and A. Morabito, Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol, 2003. 4(10): p. 605-15.
14. Wiese, F.W., P.A. Thompson, and F.F. Kadlubar, Carcinogen substrate specificity of human COX-1 and COX-2. Carcinogenesis, 2001. 22(1): p. 5-10.
15. Shirahama, T. and C. Sakakura, Overexpression of cyclooxygenase-2 in squamous cell carcinoma of the urinary bladder. Clin Cancer Res, 2001. 7(3): p. 558-61.
16. Eblin, K.E., A.M. Hau, T.J. Jensen, B.W. Futscher, and A.J. Gandolfi, The role of reactive oxygen species in arsenite and monomethylarsonous acid-induced signal transduction in human bladder cells: acute studies. Toxicology, 2008. 250(1): p. 47-54.
17. Chen, W.T., W.C. Hung, W.Y. Kang, Y.C. Huang, Y.C. Su, C.H. Yang, and C.Y. Chai, Overexpression of cyclooxygenase-2 in urothelial carcinoma in conjunction with tumor-associated-macrophage infiltration, hypoxia-inducible factor-1alpha expression, and tumor angiogenesis. APMIS, 2009. 117(3): p. 176-84.
18. Wadhwa, P., A.K. Goswami, K. Joshi, and S.K. Sharma, Cyclooxygenase-2 expression increases with the stage and grade in transitional cell carcinoma of the urinary bladder. Int Urol Nephrol, 2005. 37(1): p. 47-53.
19. Bryan, R.T., M.P. Zeegers, N.D. James, D.M. Wallace, and K.K. Cheng, Biomarkers in bladder cancer. BJU Int, 2010. 105(5): p. 608-13.
20. Plastaras, J.P., F.P. Guengerich, D.W. Nebert, and L.J. Marnett, Xenobiotic-metabolizing cytochromes P450 convert prostaglandin endoperoxide to hydroxyheptadecatrienoic acid and the mutagen, malondialdehyde. J Biol Chem, 2000. 275(16): p. 11784-90.
21. Kelley, D.J., J.R. Mestre, K. Subbaramaiah, P.G. Sacks, S.P.
Schantz, T. Tanabe, H. Inoue, J.T. Ramonetti, and A.J. Dannenberg, Benzo[a]pyrene up-regulates cyclooxygenase-2 gene expression in oral epithelial cells. Carcinogenesis, 1997. 18(4): p. 795-9.
22. Tsujii, M., S. Kawano, S. Tsuji, H. Sawaoka, M. Hori, and R.N. DuBois, Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell, 1998. 93(5): p. 705-16.
23. Dore, M., Cyclooxygenase-2 expression in animal cancers. Vet Pathol, 2011. 48(1): p. 254-65.
24. Tsujii, M. and R.N. DuBois, Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell, 1995. 83(3): p. 493-501.
25. Liu, C.H., S.H. Chang, K. Narko, O.C. Trifan, M.T. Wu, E. Smith, C. Haudenschild, T.F. Lane, and T. Hla, Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem, 2001. 276(21): p. 18563-9.
26. Weitzman, S.A. and L.I. Gordon, Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis. Blood, 1990. 76(4): p. 655-63.
27. Stolina, M., S. Sharma, Y. Lin, M. Dohadwala, B. Gardner, J. Luo, L. Zhu, M. Kronenberg, P.W. Miller, J. Portanova, J.C. Lee, and S.M. Dubinett, Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol, 2000. 164(1): p. 361-70.
28. Tsujii, M., S. Kawano, and R.N. DuBois, Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci U S A, 1997. 94(7): p. 3336-40.
29. Lai, K.C., S.C. Hsu, J.S. Yang, C.L. Kuo, S.W. Ip, T.Y. Lai, S.Y. Lin, C.C. Huang, S.C. Kuo, W.G. Wood, and J.G. Chung, 2-(3-Methoxyphenyl)-6,7-methylenedioxoquinolin-4-one, a novel synthetic compound, inhibited migration and invasion in TSGH8301 human bladder cancer cells. Hum Exp Toxicol, 2010.
30. Dohadwala, M., J. Luo, L. Zhu, Y. Lin, G.J. Dougherty, S. Sharma, M. Huang, M. Pold, R.K. Batra, and S.M. Dubinett, Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44. J Biol Chem, 2001. 276(24): p. 20809-12.
31. Chung, K.T. and P. Adris, Growth inhibition of intestinal bacteria and mutagenicity of 2-, 3-, 4-aminobiphenyls, benzidine, and biphenyl. Toxicol In Vitro, 2003. 17(2): p. 145-52.
32. Lin, T., N.K. Mak, and M.S. Yang, MAPK regulate p53-dependent cell death induced by benzo[a]pyrene: involvement of p53 phosphorylation and acetylation. Toxicology, 2008. 247(2-3): p. 145-53.
33. Reid, M.H., Laryngeal carcinoma: high-resolution computed tomography and thick anatomic sections. Radiology, 1984. 151(3): p. 689-96.
34. Chung, K.T. and C.E. Cerniglia, Mutagenicity of azo dyes: structure-activity relationships. Mutat Res, 1992. 277(3): p. 201-20.
35. Kadlubar, F.F., G. Talaska, M.A. Butler, C.H. Teitel, J.P. Massengill, and N.P. Lang, Determination of carcinogenic arylamine N-oxidation phenotype in humans by analysis of caffeine urinary metabolites. Prog Clin Biol Res, 1990. 340B: p. 107-14.
36. Chung, K.T., S.C. Chen, T.Y. Wong, Y.S. Li, C.I. Wei, and M.W. Chou, Mutagenicity studies of benzidine and its analogs: structure-activity relationships. Toxicol Sci, 2000. 56(2): p. 351-6.
37. Feng, Z., W. Hu, W.N. Rom, F.A. Beland, and M.S. Tang, 4-aminobiphenyl is a major etiological agent of human bladder cancer: evidence from its DNA binding spectrum in human p53 gene. Carcinogenesis, 2002. 23(10): p. 1721-7.
38. Clayson, D.B., T.A. Lawson, and J.A. Pringle, The carcinogenic action of 2-aminodiphenylene oxide and 4-aminodiphenyl on the bladder and liver of the C57 X IF mouse. Br J Cancer, 1967. 21(4): p. 755-62.
39. Deichmann, W.B., J. Radomski, E. Glass, W.A. Anderson, M. Coplan, and F. Woods, Synergism among Oral Carcinogens. 3. Simultaneous Feeding of Four Bladder Carcinogens to Dogs. Ind Med Surg, 1965. 34: p. 640-9.
40. Carcinogenesis Bioassay of 2-Biphenylamine Hydrochloride (CAS No. 2185-92-4) in F344/N Rats and B6C3F1 Mice (Feed Study). Natl Toxicol Program Tech Rep Ser, 1982. 233: p. 1-159.
41. Chen, S.C., C.M. Kao, M.H. Huang, M.K. Shih, Y.L. Chen, S.P. Huang, and T.Z. Liu, Assessment of genotoxicity of benzidine and its structural analogues to human lymphocytes using comet assay. Toxicol Sci, 2003. 72(2): p. 283-8.
42. Wang, S.C., J.G. Chung, C.H. Chen, and S.C. Chen, 2- and 4-Aminobiphenyls induce oxidative DNA damage in human hepatoma (Hep G2) cells via different mechanisms. Mutat Res, 2006. 593(1-2): p. 9-21.
43. Makena, P. and K.T. Chung, Evidence that 4-aminobiphenyl, benzidine, and benzidine congeners produce genotoxicity through reactive oxygen species. Environ Mol Mutagen, 2007. 48(5): p. 404-13.
44. Turesky, R.J., J.P. Freeman, R.D. Holland, D.M. Nestorick, D.W. Miller, D.L. Ratnasinghe, and F.F. Kadlubar, Identification of aminobiphenyl derivatives in commercial hair dyes. Chem Res Toxicol, 2003. 16(9): p. 1162-73.
45. Luceri, F., G. Pieraccini, G. Moneti, and P. Dolara, Primary aromatic amines from side-stream cigarette smoke are common contaminants of indoor air. Toxicol Ind Health, 1993. 9(3): p. 405-13.
46. Sun, Y. and F.A. Sinicrope, Selective inhibitors of MEK1/ERK44/42 and p38 mitogen-activated protein kinases potentiate apoptosis induction by sulindac sulfide in human colon carcinoma cells. Mol Cancer Ther, 2005. 4(1): p. 51-9.
47. Reddy, K.B., S.M. Nabha, and N. Atanaskova, Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev, 2003. 22(4): p. 395-403.
48. Kumar, B., S. Koul, J. Petersen, L. Khandrika, J.S. Hwa, R.B. Meacham, S. Wilson, and H.K. Koul, p38 mitogen-activated protein kinase-driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity. Cancer Res, 2010. 70(2): p. 832-41.
49. Kim, S.F., D.A. Huri, and S.H. Snyder, Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science, 2005. 310(5756): p. 1966-70.
50. Eschwege, P., S. Ferlicot, S. Droupy, N. Ba, M. Conti, S. Loric, G. Coindard, I. Denis, L. Ferretti, A. Cornelius, A. Legrand, P. Bedossa, G. Benoit, A. Jardin, and P. Scardino, A histopathologic investigation of PGE(2) pathways as predictors of proliferation and invasion in urothelial carcinomas of the bladder. Eur Urol, 2003. 44(4): p. 435-41.
51. Kundu, J. and Y. Surh, Molecular basis of chemoprevention by resveratrol: NF-?B and AP-1 as potential targets. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2004. 555(1-2): p. 65-80.
52. Chen, T., H. Hwang, M.E. Rose, R.G. Nines, and G.D. Stoner, Chemopreventive properties of black raspberries in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis: down-regulation of cyclooxygenase-2, inducible nitric oxide synthase, and c-Jun. Cancer Res, 2006. 66(5): p. 2853-9.
53. Kundu, J., Y. Shin, and Y. Surh, Resveratrol modulates phorbol ester-induced pro-inflammatory signal transduction pathways in mouse skinin vivo: NF-κB and AP-1 as prime targets. Biochemical Pharmacology, 2006. 72(11): p. 1506-1515.
54. Chen, F., G. Zhang, Y. Cao, M.J. Hessner, and W.A. See, MB49 murine urothelial carcinoma: molecular and phenotypic comparison to human cell lines as a model of the direct tumor response to bacillus Calmette-Guerin. J Urol, 2009. 182(6): p. 2932-7.
55. Chen, F., G. Zhang, Y. Cao, R. Payne, and W.A. See, Bacillus Calmette-Guerin inhibits apoptosis in human urothelial carcinoma cell lines in response to cytotoxic injury. J Urol, 2007. 178(5): p. 2166-70.
56. Manna, S.K., A. Mukhopadhyay, and B.B. Aggarwal, Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol, 2000. 164(12): p. 6509-19.
57. Lou, G.G., H.P. Yao, and L.P. Xie, Brucea javanica oil induces apoptosis in T24 bladder cancer cells via upregulation of caspase-3, caspase-9, and inhibition of NF-kappaB and COX-2 expressions. Am J Chin Med, 2010. 38(3): p. 613-24.
58. May, M.J. and S. Ghosh, Signal transduction through NF-kappa B. Immunol Today, 1998. 19(2): p. 80-8.
59. Li, J., Y. Cheng, W. Qu, Y. Sun, Z. Wang, H. Wang, and B. Tian, Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol, 2011. 108(2): p. 84-93.
60. Baldwin, A.S., Jr., The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol, 1996. 14: p. 649-83.
61. Langereis, J.D., H.A. Raaijmakers, L.H. Ulfman, and L.Koenderman, Abrogation of NF-kappaB signaling in human neutrophils induces neutrophil survival through sustained p38-MAPK activation. J Leukoc Biol, 2010. 88(4): p. 655-64.
62. Lallena, M.J., M.T. Diaz-Meco, G. Bren, C.V. Paya, and J. Moscat, Activation of IkappaB kinase beta by protein kinase C isoforms. Mol Cell Biol, 1999. 19(3): p. 2180-8.
63. Chen, B.C. and W.W. Lin, PKC- and ERK-dependent activation of I kappa B kinase by lipopolysaccharide in macrophages: enhancement by P2Y receptor-mediated CaMK activation. Br J Pharmacol, 2001. 134(5): p. 1055-65.
64. Vermeulen, L., G. De Wilde, S. Notebaert, W. Vanden Berghe, and G. Haegeman, Regulation of the transcriptional activity of the nuclear factor-kappaB p65 subunit. Biochem Pharmacol, 2002. 64(5-6): p. 963-70.
65. Fridovich, I., Superoxide radicals, superoxide dismutases and the aerobic lifestyle. Photochem Photobiol, 1978. 28(4-5): p. 733-41.
66. Papa, S. and V.P. Skulachev, Reactive oxygen species, mitochondria, apoptosis and aging. Mol Cell Biochem, 1997. 174(1-2): p. 305-19.
67. Wing, L.Y., Y.C. Chen, Y.Y. Shih, J.C. Cheng, Y.J. Lin, and M.J. Jiang, Effects of oral estrogen on aortic ROS-generating and -scavenging enzymes and atherosclerosis in apoE-deficient mice. Exp Biol Med (Maywood), 2009. 234(9): p. 1037-46.
68. Liu, Y., W. Zhang, X. Zhang, Y. Qi, D. Huang, and Y. Zhang, Arsenic trioxide inhibits invasion/migration in SGC-7901 cells by activating the reactive oxygen species-dependent cyclooxygenase-2/matrix metalloproteinase-2 pathway. Exp Biol Med (Maywood), 2011. 236(5): p. 592-7.
69. Jung, C.H., C.Y. Jun, S. Lee, C.H. Park, K. Cho, and S.G. Ko, Rhus verniciflua stokes extract: radical scavenging activities and protective effects on H2O2-induced cytotoxicity in macrophage RAW 264.7 cell lines. Biol Pharm Bull, 2006. 29(8): p. 1603-7.
70. Alexandrova, A.Y., P.B. Kopnin, J.M. Vasiliev, and B.P. Kopnin, ROS up-regulation mediates Ras-induced changes of cell morphology and motility. Exp Cell Res, 2006. 312(11): p. 2066-73.
71. Wu, W.S., The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev, 2006. 25(4): p. 695-705.
72. Weisburger, J.H., Comments on the history and importance of aromatic and heterocyclic amines in public health. Mutat Res, 2002. 506-507: p. 9-20.
73. Kole, L., B. Giri, S.K. Manna, B. Pal, and S. Ghosh, Biochanin-A, an isoflavon, showed anti-proliferative and anti-inflammatory activities through the inhibition of iNOS expression, p38-MAPK and ATF-2 phosphorylation and blocking NFkappaB nuclear translocation. Eur J Pharmacol, 2011. 653(1-3): p. 8-15.
74. Maziere, C., V. Savitsky, A. Galmiche, C. Gomila, Z. Massy, and J.C. Maziere, Oxidized low density lipoprotein inhibits phosphate signaling and phosphate-induced mineralization in osteoblasts. Involvement of oxidative stress. Biochim Biophys Acta, 2010. 1802(11): p. 1013-9.
75. Richter, C., Reactive oxygen and nitrogen species regulate mitochondrial Ca2+ homeostasis and respiration. Biosci Rep, 1997. 17(1): p. 53-66.
76. Schulman, I.H. and J.M. Hare, Regulation of cardiovascular cellular processes by S-nitrosylation. Biochim Biophys Acta, 2011.
77. Tousoulis, D., A. Briasoulis, N. Papageorgiou, C. Tsioufis, E. Tsiamis, K. Toutouzas, and C. Stefanadis, Oxidative Stress and Endothelial Function: Therapeutic Interventions. Recent Pat Cardiovasc Drug Discov, 2011.
78. Han, D., F. Antunes, R. Canali, D. Rettori, and E. Cadenas, Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J Biol Chem, 2003. 278(8): p. 5557-63.
79. Rada, B. and T.L. Leto, Oxidative innate immune defenses by Nox/Duox family NADPH oxidases. Contrib Microbiol, 2008. 15: p. 164-87.
80. Williams, H.C. and K.K. Griendling, NADPH oxidase inhibitors: new antihypertensive agents? J Cardiovasc Pharmacol, 2007. 50(1): p. 9-16.
81. Sun, H.N., S.U. Kim, M.S. Lee, S.K. Kim, J.M. Kim, M. Yim, D.Y. Yu, and D.S. Lee, Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent activation of phosphoinositide 3-kinase and p38 mitogen-activated protein kinase signal pathways is required for lipopolysaccharide-induced microglial phagocytosis. Biol Pharm Bull, 2008. 31(9): p. 1711-5.
82. Mustapha, N.M., J.M. Tarr, E.M. Kohner, and R. Chibber, NADPH Oxidase versus Mitochondria-Derived ROS in Glucose-Induced Apoptosis of Pericytes in Early Diabetic Retinopathy. J Ophthalmol, 2010. 2010: p. 746978.
83. Wu, F., K. Tyml, and J.X. Wilson, iNOS expression requires NADPH oxidase-dependent redox signaling in microvascular endothelial cells. J Cell Physiol, 2008. 217(1): p. 207-14.
84. Leusen, J.H., A.J. Verhoeven, and D. Roos, Interactions between the components of the human NADPH oxidase: a review about the intrigues in the phox family. Front Biosci, 1996. 1: p. d72-90.
85. Gorlach, A., I. Diebold, V.B. Schini-Kerth, U. Berchner-Pfannschmidt, U. Roth, R.P. Brandes, T. Kietzmann, and R. Busse, Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular smooth muscle cells: Role of the p22(phox)-containing NADPH oxidase. Circ Res, 2001. 89(1): p. 47-54.
86. Li, L., G.D. Fink, S.W. Watts, C.A. Northcott, J.J. Galligan, P.J. Pagano, and A.F. Chen, Endothelin-1 increases vascular superoxide via endothelin(A)-NADPH oxidase pathway in low-renin hypertension. Circulation, 2003. 107(7): p. 1053-8.
87. Loomis, E.D., J.C. Sullivan, D.A. Osmond, D.M. Pollock, and J.S. Pollock, Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta. J Pharmacol Exp Ther, 2005. 315(3): p. 1058-64.
88. Wang, Y., W. Wang, L. Wang, X. Wang, and J. Xia, Regulatory mechanisms of interleukin 8 production induced by tumor necrosis factor-alpha in human hepatocellular carcinoma cells. J Cell Mol Med, 2011.
89. Jang, B.C., Induction of COX-2 in human airway cells by manganese: role of PI3K/PKB, p38 MAPK, PKCs, Src, and glutathione depletion. Toxicol In Vitro, 2009. 23(1): p. 120-6.
90. Shaulian, E. and M. Karin, AP-1 as a regulator of cell life and death. Nat Cell Biol, 2002. 4(5): p. E131-6.
91. Jochum, W., E. Passegue, and E.F. Wagner, AP-1 in mouse development and tumorigenesis. Oncogene, 2001. 20(19): p. 2401-12.
92. Eferl, R. and E.F. Wagner, AP-1: a double-edged sword in
tumorigenesis. Nat Rev Cancer, 2003. 3(11): p. 859-68.
93. Komhoff, M., Y. Guan, H.W. Shappell, L. Davis, G. Jack, Y. Shyr, M.O. Koch, S.B. Shappell, and M.D. Breyer, Enhanced expression of cyclooxygenase-2 in high grade human transitional cell bladder carcinomas. Am J Pathol, 2000. 157(1): p. 29-35.
94. Ricicki, E.M., W. Luo, W. Fan, L.P. Zhao, H. Zarbl, and P. Vouros, Quantification of N-(deoxyguanosin-8-yl)-4-aminobiphenyl adducts in human lymphoblastoid TK6 cells dosed with N-hydroxy-4-acetylaminobiphenyl and their relationship to mutation, toxicity, and gene expression profiling. Anal Chem, 2006. 78(18): p. 6422-32.
95. Murata, M. and S. Kaw Anishi, Mechanisms of oxidative DNA damage induced by carcinogenic arylamines. Front Biosci, 2011. 16: p. 1132-43.
96. Schorp, M.K. and D.E. Leyden, Biomonitoring of smoke constituents: exposure to 4-aminobiphenyl and 4-aminobiphenyl hemoglobin adduct levels in nonsmokers and smokers. Inhal Toxicol, 2010. 22(9): p. 725-37.
97. Chung, S.W., H.Y. Chung, A. Toriba, T. Kameda, N. Tang, R. Kizu, and K. Hayakawa, An environmental quinoid polycyclic aromatic hydrocarbon, acenaphthenequinone, modulates cyclooxygenase-2 expression through reactive oxygen species generation and nuclear factor kappa B activation in A549 cells. Toxicol Sci, 2007. 95(2): p. 348-55.
98. Yang, C., H. Ling, M. Zhang, Z. Yang, X. Wang, F. Zeng, C. Wang, and J. Feng, Oxidative stress mediates chemical hypoxia-induced injury and inflammation by activating NF-kappab-COX-2 pathway in HaCaT cells. Mol Cells, 2011. 31(6): p. 531-8.
99. Babior, B.M., J.D. Lambeth, and W. Nauseef, The neutrophil NADPH oxidase. Arch Biochem Biophys, 2002. 397(2): p. 342-4.
100. Syed, I., C.N. Kyathanahalli, and A. Kowluru, Phagocyte-like NADPH oxidase generates ROS in INS 832/13 cells and rat islets: role of protein prenylation. Am J Physiol Regul Integr Comp Physiol, 2011. 300(3): p. R756-62.
101. Masai, N., J. Tatebe, G. Yoshino, and T. Morita, Indoxyl sulfate stimulates monocyte chemoattractant protein-1 expression in human umbilical vein endothelial cells by inducing oxidative stress through activation of the NADPH oxidase-nuclear factor-kappaB pathway. Circ J, 2010. 74(10): p. 2216-24.
102. Ambasta, R.K., P. Kumar, K.K. Griendling, H.H. Schmidt, R. Busse, and R.P. Brandes, Direct interaction of the novel Nox proteins with p22phox is required for the formation of a functionally active NADPH oxidase. J Biol Chem, 2004. 279(44): p. 45935-41.
103. Bedard, K. and K.H. Krause, The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev, 2007. 87(1): p. 245-313.
104. Cattaneo, F., A. Iaccio, G. Guerra, S. Montagnani, and R. Ammendola, NADPH-oxidase-dependent reactive oxygen species mediate EGFR transactivation by FPRL1 in WKYMVm-stimulated human lung cancer cells. Free Radic Biol Med, 2011.
105. Autore, F., B. Pagano, A. Fornili, K. Rittinger, and F. Fraternali, In silico phosphorylation of the autoinhibited form of p47(phox): insights into the mechanism of activation. Biophys J, 2010. 99(11): p. 3716-25.
106. Edderkaoui, M., C. Nitsche, L. Zheng, S.J. Pandol, I. Gukovsky, and A.S. Gukovskaya, NADPH oxidase activation in pancreatic cancer cells is mediated through Akt-dependent up-regulation of p22phox. J Biol Chem, 2011. 286(10): p. 7779-87.
107. Block, K., Y. Gorin, D.D. New, A. Eid, T. Chelmicki, A. Reed, G.G. Choudhury, D.J. Parekh, and H.E. Abboud, The NADPH oxidase subunit p22phox inhibits the function of the tumor suppressor protein tuberin. Am J Pathol, 2010. 176(5): p. 2447-55.
108. Tsai, K.S., R.S. Yang, and S.H. Liu, Benzo[a]pyrene regulates osteoblast proliferation through an estrogen receptor-related cyclooxygenase-2 pathway. Chem Res Toxicol, 2004. 17(5): p. 679-84.
109. Kumar, B., J. Sinclair, L. Khandrika, S. Koul, S. Wilson, and H.K. Koul, Differential effects of MAPKs signaling on the growth of invasive bladder cancer cells. Int J Oncol, 2009. 34(6): p. 1557-64.
110. Surh, Y.J., K.S. Chun, H.H. Cha, S.S. Han, Y.S. Keum, K.K. Park, and S.S. Lee, Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res, 2001. 480-481: p. 243-68.
111. Lin, C.C., I.T. Lee, Y.L. Yang, C.W. Lee, Y.R. Kou, and C.M. Yang, Induction of COX-2/PGE(2)/IL-6 is crucial for cigarette smoke extract-induced airway inflammation: Role of TLR4-dependent NADPH oxidase activation. Free Radic Biol Med, 2010. 48(2): p. 240-54.
112. Choudhary, S., K. Rathore, and H.C. Wang, Differential induction of reactive oxygen species through Erk1/2 and Nox-1 by FK228 for selective apoptosis of oncogenic H-Ras-expressing human urinary bladder cancer J82 cells. J Cancer Res Clin Oncol, 2011. 137(3): p. 471-80.
113. Dreiem, A., S. Rykken, H.J. Lehmler, L.W. Robertson, and F. Fonnum, Hydroxylated polychlorinated biphenyls increase reactive oxygen species formation and induce cell death in cultured cerebellar granule cells. Toxicol Appl Pharmacol, 2009. 240(2): p. 306-13.
114. Gesser, B., M.K. Rasmussen, L. Raaby, C. Rosada, C. Johansen, R.B. Kjellerup, K. Kragballe, and L. Iversen, Dimethylfumarate inhibits MIF-induced proliferation of keratinocytes by inhibiting MSK1 and RSK1 activation and by inducing nuclear p-c-Jun (S63) and p-p53 (S15) expression. Inflamm Res, 2011.
115. Sui, H., S. Zhou, Y. Wang, X. Liu, L. Zhou, P. Yin, Z. Fan, and Q. Li, COX-2 contributes to P-glycoprotein-mediated multidrug resistance via phosphorylation of c-Jun at Ser63/73 in colorectal cancer. Carcinogenesis, 2011. 32(5): p. 667-75.
116. Li, Q., N. Liu, B. Shen, L. Zhou, Y. Wang, J. Sun, Z. Fan, and R.H. Liu, Helicobacter pylori enhances cyclooxygenase 2 expression via p38MAPK/ATF-2 signaling pathway in MKN45 cells. Cancer Lett, 2009. 278(1): p. 97-103.
117. Tung, W.H., I.T. Lee, H.L. Hsieh, and C.M. Yang, EV71 induces COX-2 expression via c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK/AP-1 and NF-kappaB in rat brain astrocytes. J Cell Physiol, 2010. 224(2): p. 376-86.
118. Lu, D.Y., Y.M. Leung, S.M. Huang, and K.L. Wong, Bradykinin-induced cell migration and COX-2 production mediated by the bradykinin B1 receptor in glioma cells. J Cell Biochem, 2010. 110(1): p. 141-50.