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  • Original Paper
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Induction of cyclooxygenase-2 by benzo[a]pyrene diol epoxide through inhibition of retinoic acid receptor-β2 expression

Abstract

Benzo[a]pyrene diol epoxide (BPDE, a carcinogen present in tobacco smoke and environmental pollution) has been shown to suppress retinoic acid receptor-beta2 (RAR-β2) and induce cyclooxygenase-2 (COX-2) expression. Restoration of RAR-β2 inhibited growth and colony formation of esophageal cancer cells, which was correlated with COX-2 suppression. In this study, we investigated the molecular mechanisms for RAR-β2-mediated suppression of COX-2 expression using BPDE as a tool. We found that BPDE-induced COX-2 expression was through inhibition of RAR-β2 and consequently, induction of epidermal growth factor receptor (EGFR), extracellular signal-regulated protein kinases 1/2 (Erk1/2) phosphorylation, and c-Jun expression. Esophageal cancer cells that do not express RAR-β2 did not respond to BPDE for induction of COX-2. BPDE was also unable to induce COX-2 expression after RAR-β2 expression was manipulated in these esophageal cancer cells. Furthermore, BPDE induced time-dependent methylation of RAR-β2 gene promoter in esophageal cancer cells. Transfection of RAR-β2 expression vector into esophageal cancer cells suppressed expression of EGFR, Erk1/2 phosphorylation, c-Jun, and COX-2. In addition, co-treatment of RAR-β2-positive cells with BPDE and the MEK1/2 inhibitor U0126 caused little change in c-Jun and COX-2 expression. This study demonstrated that BPDE-suppressed expression of RAR-β2 results in COX-2 induction and restoration of RAR-β2 expression reduces COX-2 protein in esophageal cancer cells, thereby further supporting our previous finding that RAR-β2 plays an important role in suppressing esophageal carcinogenesis.

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References

  • Alberts D, Ranger-Moore J, Einspahr J, Saboda K, Bozzo P, Liu Y, Xu X-C, Lotan R, Warneke J, Salasche S, Stratton S, Levine N, Goldman R, Islas M, Duckett L, Thompson D and Bartels P . (2004). Clin. Cancer Res., 10, 1875–1880.

  • Ayoub J, Jean-Francois R, Cormier Y, Meyer D, Ying Y, Major P, Desjardins C and Bradley WE . (1999). J. Clin. Oncol., 17, 3546–3552.

  • Berard J, Laboune F, Mukuna M, Masse S, Kothary R and Bradley WE . (1996). FASEB J., 10, 1091–1097.

  • Berg WJ, Nanus DM, Leung A, Brown KT, Hutchinson B, Mazumdar M, Xu X-C, Lotan R, Reuter VE and Motzer RJ . (1999). Clin. Cancer Res., 5, 1671–1675.

  • Cote S, Sinnett D and Momparler RL . (1998). Anticancer Drugs, 9, 743–750.

  • DeVita Jr VT, Hellman S and Rosenberg SA (eds) (1997). Cancer: Principles and Practice of Oncology. Lippincott-Raven Publishers: Philadelphia and New York.

    Google Scholar 

  • Dragnev KH, Petty WJ and Dmitrovsky E . (2003). Cancer Biol. Ther., 2, S150–S156.

  • Enzinger PC and Mayer RJ . (2003). N. Engl. J. Med., 349, 2241–2252.

  • Faria TN, Mendelsohn C, Chambon P and Gudas LJ . (1999). J. Biol. Chem., 274, 26783–26778.

  • Gebert JF, Moghal N, Frangioni JV, Sugarbaker DJ and Neel BG . (1991). Oncogene, 6, 1859–1868.

  • Grandis JR, Zeng Q and Tweardy DJ . (1996). Nat. Med., 2, 237–240.

  • Houle B, Rochette-Egly C and Bradley WE . (1993). Proc. Natl. Acad. Sci. USA, 90, 985–989.

  • Khuri FR, Wu H, Lee JJ, Kemp BL, Lotan R, Lippman SM, Feng L, Hong WK and Xu XC . (2001). Clin. Cancer Res., 7, 861–867.

  • Kim YT, Lee SH, Sung SW and Kim JH . (2005). Ann. Thorac. Surg., 79, 1180–1188.

  • Koch TR . (2003). Curr. Gastroenterol. Rep., 5, 187–191.

  • Kong G, Kim HT, Wu K, DeNardo D, Hilsenbeck SG, Xu XC, Lamph WW, Bissonnette R, Dannenberg AJ and Brown PH . (2005). Cancer Res., 65, 3462–3469.

  • Kurie JM, Lee JS, Khuri FR, Mao L, Morice RC, Lee JJ, Walsh GL, Broxson A, Lippman SM, Ro JY, Kemp BL, Liu D, Fritsche HA, Xu X-C, Lotan R and Hong WK . (2000). Clin. Cancer Res., 6, 2973–2979.

  • Kurie JM, Lotan R, Lee JJ, Lee JS, Morice RC, Liu D, Xu X-C, Khuri FR, Ro JY, Hittelman WN, Walsh GL, Roth JA, Minna JD and Hong WK . (2003). J. Natl. Cancer Inst., 95, 206–214.

  • Kuroki T, Trapasso F, Yendamuri S, Matsuyama A, Alder H, Mori M and Croce CM . (2003). Cancer Res., 63, 3724–3728.

  • Lam S, Xu X-C, Parker-Klein H, Le Riche JC, Macaulay C, Guillaud M, Coldman A, Gazdar A and Lotan R . (2003). Int. J. Oncol., 23, 1607–1613.

  • Lango M, Wentzel AL, Song JI, Xi S, Johnson DE, Lamph WW, Miller L and Grandis JR . (2003). Clin. Cancer Res., 9, 4205–4213.

  • Li M, Song S, Lippman SM, Zhang XK, Liu X, Lotan R and Xu X-C . (2002). Oncogene, 21, 411–418.

  • Lin B, Chen GQ, Xiao D, Kolluri SK, Cao X, Su H and Zhang XK . (2000a). Mol. Cell. Biol., 20, 957–970.

  • Lin F, Xiao D, Kolluri SK and Zhang X . (2000b). Cancer Res., 60, 3271–3280.

  • Liu ZM, Ding F, Guo MZ, Zhang LY, Wu M and Liu ZH . (2004). World J. Gastroenterol., 10, 771–775.

  • Lotan R, Xu X-C, Lippman SM, Ro JY, Lee JS, Lee JJ and Hong WK . (1995). N. Engl. J. Med., 332, 1405–1410.

  • Lotan Y, Xu X-C, Shalev M, Lotan R, Williams R, Wheeler TM, Thompson TC and Kadmon D . (2000). J. Clin. Oncol., 18, 116–121.

  • Mayne ST and Navarro SA . (2002). J. Nutr., 132, S3467–S3470.

  • McCann J . (1999). J. Natl. Cancer Inst., 91, 497–498.

  • McGregor F, Muntoni A, Fleming J, Brown J, Felix DH, MacDonald DG, Parkinson EK and Harrison PR . (2002). Cancer Res., 62, 4757–4766.

  • Mechta-Grigoriou F, Gerald D and Yaniv M . (2001). Oncogene, 20, 2378–2389.

  • Pfarr CM, Mechta F, Spyrou G, Lallemand D, Carillo S and Yaniv M . (1994). Cell, 76, 747–760.

  • Posner MC (eds) (2002). Cancer of the Upper Gastrointestinal Tract. American Cancer Society: Atlanta.

    Google Scholar 

  • Qiu H, Lotan R, Lippman SM and Xu X-C . (2000). Genes Chromosomes Cancer, 28, 196–202.

  • Qiu H, Zhang W, El-Naggar AK, Lippman SM, Lin P, Lotan R and Xu X-C . (1999). Am. J. Pathol., 155, 1519–1523.

  • Richter JE . (1999). Clinical Practice of Gastroenterology, Vol. 1. Brandt LJ (ed). Churchill Livingstone: Philadelphia, pp. 1–150.

    Google Scholar 

  • Sah JF, Eckert RL, Chandraratna RA and Rorke EA . (2002). J. Biol. Chem., 277, 9728–9735.

  • Shaulian E and Karin M . (2001). Oncogene, 20, 2390–2400.

  • Song S and Xu XC . (2001). Biochem. Biophys. Res. Commun., 281, 872–877.

  • Su H, Hu N, Shih J, Hu Y, Wang QH, Chuang EY, Roth MJ, Wang C, Goldstein AM, Ding T, Dawsey SM, Giffen C, Emmert-Buck MR and Taylor PR . (2003). Cancer Res., 63, 3872–3876.

  • The US Surgeon General Report (2004). www.surgeongeneral.gov.

  • Toulouse A, Loubeau M, Morin J, Pappas JJ, Wu J and Bradley WE . (2000). FASEB J., 14, 1224–1232.

  • Virmani AK, Rathi A, Zochbauer-Muller S, Sacchi N, Fukuyama Y, Bryant D, Maitra A, Heda S, Fong KM, Thunnissen F, Minna JD and Gazdar AF . (2000). J. Natl. Cancer Inst., 92, 1303–1307.

  • Wang XD, Liu C, Bronson RT, Smith DE, Krinsky NI and Russell M . (1999). J. Natl. Cancer Inst., 91, 60–66.

  • Wang Y, Fang MZ, Liao J, Yang GY, Nie Y, Song Y, So C, Xu X-C, Wang LD and Yang CS . (2003). Clin. Cancer Res., 9, 5257–5263.

  • Widschwendter M, Berger J, Hermann M, Muller HM, Amberger A, Zeschnigk M, Widschwendter A, Abendstein B, Zeimet AG, Daxenbichler G and Marth C . (2000). J. Natl. Cancer Inst., 92, 826–832.

  • Wu Q, Li Y, Liu R, Agadir A, Lee MO, Liu Y and Zhang X . (1997). EMBO J., 16, 1656–1669.

  • Xu M, Jin YL, Fu J, Huang H, Chen SZ, Qu P, Tian HM, Liu ZY and Zhang W . (2002a). World J. Gastroenterol., 8, 200–202.

  • Xu X-C . (2002). Anti-Cancer Drugs, 13, 127–137.

  • Xu X-C and Lotan R . (1999). Handbook of Experimental Pharmacology. Nau H and Blaner WS (eds). Springer: Berlin and New York, pp. 323–343.

    Google Scholar 

  • Xu X-C, Lee JS, Lee JJ, Morice RC, Liu X, Lippman SM, Hong WK and Lotan R . (1999a). J. Natl. Cancer Inst., 91, 1317–1321.

  • Xu X-C, Liu X, Tahara E, Lippman SM and Lotan R . (1999b). Cancer Res., 59, 2477–2483.

  • Xu X-C, Zhang W, Song S, Lotan R and Lippman SM . (2002b). Cancer Epidemiol. Biomark. Prev., 11, A120.

  • Yang-Yen HF, Zhang XK, Graupner G, Tzukerman M, Sakamoto B, Karin M and Pfahl M . (1991). New Biol., 3, 1206–1219.

  • Zhang W, Rashid A, Wu H and Xu XC . (2001). J. Cancer Res. Clin. Oncol., 127, 237–242.

  • Zhuang Y, Faria TN, Chambon P and Gudas LJ . (2003). Mol. Cancer Res., 1, 619–630.

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Acknowledgements

This study was supported by Jerry and Maury Rubenstein Foundation and UT MD Anderson Cancer Center Multidisciplinary Research Program. We thank the Department of Scientific Publications for editing the manuscript.

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Correspondence to Xiao-chun Xu.

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Song, S., Lippman, S., Zou, Y. et al. Induction of cyclooxygenase-2 by benzo[a]pyrene diol epoxide through inhibition of retinoic acid receptor-β2 expression. Oncogene 24, 8268–8276 (2005). https://doi.org/10.1038/sj.onc.1208992

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