Abstract
Selective cyclooxygenase-2 (COX-2) inhibitors are promising anti-inflammatory drugs with potential antitumor activities. The nuclear factor-kappa B (NF-κB) family of proteins is important transcriptional regulators of genes involved in immunity, inflammation, and carcinogenesis. In the present study, we investigated whether and by which molecular mechanism the selective COX-2 inhibitors inhibit NF-κB activation in gastric cancer. The effects of SC236 and its derivative, but devoid of COX-2 enzyme inhibition activity on NF-κB signaling, were evaluated using electromobility shift, transfection, and reporter gene assay. The translocation of RelA/p65 was investigated using Western blotting and immunocytochemistry. We showed that SC236 suppressed NF-κB-mediated gene transcription and binding activity in gastric cancer. This effect occurred through a mechanism independent of cyclooxygenase activity and prostaglandin synthesis. Furthermore, unlike aspirin, SC236 affected neither the phosphorylation, degradation, nor expression of IκB-α, suggesting that the effects of SC236 are independent of IKK activity and IκB-α gene transcription. Instead, SC236 worked directly through suppressing nuclear translocation of RelA/p65. It is possible that SC236 directly targets proteins that facilitate the nuclear translocation of NF-κB. Our study suggests an important molecular mechanism by which COX-2 inhibitors reduce inflammation and suppress carcinogenesis in gastrointestinal tract.
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References
Baldwin Jr AS (1996). Annu. Rev. Immunol., 14, 649–681.
Barnes PJ and Karin M . (1997). N. Engl. J. Med., 336, 1066–1071.
Beg AA, Sha WC, Bronson RT, Ghosh S and Baltimore D . (1995). Nature, 376, 167–170.
Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH and Ballard DW . (1997). Prog. Natl. Acad. Sci. USA, 94, 10057–10062.
Connolly EM, Harmey JH, O'Grady T, Foley D, Roche-Nagle G, Kay E, Bouchier-Hayes DJ . (2002). Br. J. Cancer, 87(2) 231–237.
Dignam JD, Lebovitz RM and Roeder RG . (1983). Nucleic Acids Res., 11, 1475–1489.
DuBois RN and Smalley WE (1996). J. Gastroenterol., 31, 898–906.
Elder DJ, Halton DE, Hague A and Paraskeva C . (1997). Clin. Cancer Res., 3, 1679–1683.
Grilli MJ, Pizzi M, Memo M and Spano P . (1996). Science, 274, 1383–1385.
Grosch S, Tegeder I, Niederberger E, Brautigam L, Geisslinger G . (2001). FASEB J., 15(14) 2742–2744.
Gupta RA and DuBois RN . (1998). Gastroenterology, 114, 1095–1098.
Hanif R, Pittas A, Feng Y, Koutsos MI, Qiao L, Staiano-Caico L, Shiff SI, Rigas B . (1996). Biochem. Pharmacol., 52, 237–245.
He TC, Chan TA, Vogelstein B and Kinzler KW . (1999). Cell, 99, 335–345.
Hsu AL, Ching TT, Wang DS, Song X, Rangnekar VM, Chen CS . (2000). J. Biol. Chem., 275(15) 11397–11403.
Jiang XH, Lam SK, Lin MCM, Jiang SH, Kung HF, Slosberg ED, Soh JW, Weinstein IB and Wong BCY . (2002). Oncogene, 21, 6113–6122.
Kargman SL, O'Neill GP, Vichers PJ, Evans JF, Mancini JA and Jothy S . (1995). Cancer Res., 55, 3785–3789.
Kopp E and Ghosh S . (1994). Science, 265, 956–959.
Li JJ, Westergaard C, Ghosh P and Colburn NH . (1997). Cancer Res., 57, 3569–3576.
Manna SK, Mukhopadhyay A and Aggarwal BB . (2000). J. Immunol.,164, 6509–6519.
Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, Edwards DA, Flickinger AG, Moore RJ and Seibert K (2000). Cancer Res., 60, 1306–1311.
Natarajan K, Singh S, Burke Jr TR, Grunberger D and Aggarwal BB . (1996). Proc. Natl. Acad. Sci. USA, 93, 9090–9095.
Parett ML, Harris RE, Joarder FS, Ross MS, Clausen KP and Robertson FM . (1997). Int. J. Oncol., 10, 503–507.
Penning TD, Talley JJ, Bertenshaw SR, Carter JS, Collins PW and Docter S . (1997). J. Med. Chem., 40, 1347–1365.
Reddy BS, Rao CV and Seibert K . (1996). Cancer Res., 56, 4566–4569.
Richter M, Weiss M, Weinberger I, Furstenberger G and Marian B . (2001). Carcinogenesis, 22(1) 17–25.
Ristimaki A, Honkanen N, Jankala H, Sipponen P and Harkonen M . (1997). Cancer Res., 57, 1276–1281.
Sawaoka H, Kawano S, Tsuji S, Tsuji M, Gunawan ES, Takei Y, Nagano K and Hori M . (1998). Am. J. Physiol., 274, G1061–G1065.
Sheng H, Shao J, Morrow JD, Beauchamp RD and DuBois RN . (1998). Cancer Res., 58, 362–366.
Stark LA, Din FVN, Zwacka RM and Dunlop MG . (2001). FASEB J., 15, 1273–1275.
Tegeder I, Niederberger E, Israr E, Guhring H, Brune K, Euchenhofer C, Grosch S and Geisslinger G . (2001). FASEB J., 15, 2–4.
Vane JR . (1971). Nat. New Biol., 231, 232–235.
Wahl C, Liptay S, Adler G and Schmid RM . (1998). J. Clin. Invest., 101, 1163–1174.
Wang CY, Mayo MW, Korneluk RG, Goeddel DV and Baldwin Jr AS . (1998). Science, 281, 1680–1683.
Weber CK, Liptay S, Wirth T, Adler G and Schmid RM . (2000). Gastroenterology, 119, 1209–1218.
Wulczyn FG, Krappmann D and Scheidereit C . (1996). J. Mol. Med., 74, 749–769.
Yamamoto Y, Yin MJ, Lin KM and Gaynor RB . (1999). J. Biol. Chem., 274, 27307–27314.
Yin MJ, Yamamoto Y and Gaynor RB . (1998). Nature, 396, 77–80.
Zhou XM, Wong BCY, Fan XM, Zhang HB, Lin MCM, Kung HF, Fan DM and Lam SK . (2001). Carcinogenesis., 22(9) 1393–1397.
Zhu GH, Wong BCY, Eggo MC, Ching CK, Yuen ST, Chan EYT, Lai KC and Lam SK . (1999). Br. J. Cancer., 79, 393–400.
Zhu GH, Wong BCY, Slosberg ED, Eggo MC, Ching CK, Yuen ST, Lai KC, Soh JW, Weinstein IB and Lam SK . (2000). Gastroenterology, 118, 507–514.
Acknowledgements
This study is supported by Research Grant Council earmarked Grant HKU 7010/99 M and HKU 7309/01 M of the Hong Kong Special Administration Region, and the Gastroenterogical Research Fund, University of Hong Kong.
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Wong, B., Jiang, X., Fan, X. et al. Suppression of RelA/p65 nuclear translocation independent of IκB-α degradation by cyclooxygenase-2 inhibitor in gastric cancer. Oncogene 22, 1189–1197 (2003). https://doi.org/10.1038/sj.onc.1206234
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DOI: https://doi.org/10.1038/sj.onc.1206234
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