Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-κB activation via the NIK/IKK signalling complex

Abstract

Colorectal cancer is a major cause of cancer deaths in Western countries, but epidemiological data suggest that dietary modification might reduce these by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of prostaglandin H synthase, which mediates prostaglandin synthesis during inflammation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-inflammatory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully understood. We found that in human colon epithelial cells, curcumin inhibits COX2 induction by the colon tumour promoters, tumour necrosis factor α or fecapentaene-12. Induction of COX2 by inflammatory cytokines or hypoxia-induced oxidative stress can be mediated by nuclear factor kappa B (NF-κB). Since curcumin inhibits NF-κB activation, we examined whether its chemopreventive activity is related to modulation of the signalling pathway which regulates the stability of the NF-κB-sequestering protein, IκB. Recently components of this pathway, NF-κB-inducing kinase and IκB kinases, IKKα and β, which phosphorylate IκB to release NF-κB, have been characterised. Curcumin prevents phosphorylation of IκB by inhibiting the activity of the IKKs. This property, together with a long history of consumption without adverse health effects, makes curcumin an important candidate for consideration in colon cancer prevention.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

Abbreviations

NF-κB:

nuclear factor kappa B

COX-2:

cyclo-oxygenase-2

TNFα:

tumour necrosis factor alpha

FEC:

fecapentaene-12

PMA:

phorbol 12-myristate 13-acetate

CUR:

curcumin

SAL:

salicylate

CAPE:

caffeic acid phenyl ester

NAC:

N-acetyl cysteine

NIK:

NF-κB inducing kinase

IKK:

I kappa B kinase

EMSA:

electrophoretic mobility gel shift assay

ANOVA:

analysis of variance

References

  • Beg AA and Baltimore D. . 1996 Science 274: 783–784.

  • Bierhaus A, Zhang Y, Quehenberger P, Luther T, Haase M, Muller M, Mackman N, Zeigler R and Nawroth PP. . 1997 Thromb. Haemo. 77: 772–782.

  • Braegger CP, Nicholls S, Murch SH, Stephens S and MacDonald TT. . 1992 Lancet 339: 89–91.

  • Cohen L, Henzel WJ and Baeuerle PA. . 1998 Nature 395: 292–296.

  • Crofford LJ, Tan B, McCarthy CJ and Hla T. . 1997 Arthritis Rheum. 40: 226–236.

  • Diaz-Meco MT, Berra E, Municio MM, Sanz I and Lozano J. . 1993 Mol. Cell. Biol. 13: 4770–4775.

  • DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E and Karin M. . (1997) Nature 388: 548–554.

  • Du M, Xu XM, Sansores-Garcia L, Zu Z and Wu KK. . 1998 Blood 92: 2253.

  • Dubois RN and Smalley WE. . 1996 J. Gastroenterol. 31: 898–906.

  • Eberhart CE and DuBois RN. . 1995 Gastroenterol. 109: 285–301.

  • Gardiello FM, Hamilton SR, Hylind LM, Yang VW, Tamez P and Casero RA. . 1997 Cancer Res. 57: 199–201.

  • Ghosh S and Baltimore D. . 1990 Nature 344: 678–682.

  • Giardiello FM, Offerhaus GJA and Dubois RN. . 1995 Eur. J. Cancer 31A: 1071–1076.

  • Gyde SN, Prior P, Allan RN, Stevens A, Jewell DP, Truelove SC, Lofberg R, Brostrom O and Hellers G. . 1998 Gut 29: 206–217.

  • Hershman HR. . 1994 Cancer Metast. Rev. 13: 241–256.

  • Hla T and Maciag T. . 1991 J. Biol. Chem. 266: 24059–24063.

  • Holloway K, Munks RJL, Peer M-A and Plummer SM. . 1998 Br. J. Cancer 78: 157.

  • Hoshina S, Ueffing M, Morotomi M and Weinstein IB. . 1991 Biochem. Biophys. Res. Commun. 176: 505–510.

  • Huang M-T, Lysz T, Ferraro T and Conney AH. . 1992 In: Cancer Chemoprevention, Wattenberg L, Lipkin M, Boone CW and Kelloff (eds). CRC Press Inc. pp.375–391.

  • Huang TS, Lee SC and Lin JK. . 1991 Proc. Natl. Acad.Sci. USA 88: 5292–5296.

  • Kargman SL, O'Neill GP, Vickers PJ, Evans JF, Mancini JA and Jothy S. . 1995 Cancer Res. 55: 2556–2559.

  • Kawamori T, Rao CV, Seibert K and Reddy BS. . 1998 Cancer Res. 58: 409–412.

  • Kelley DJ, Sacks PG, Ramonetti JT, Schantz SP and Dannenberg AJ. . 1996 Proc. Am. Assoc. Cancer Res. 37: 909.

  • Kopp E and Ghosh S. . 1994 Science 265: 956–959.

  • Kumar A, Dhawan S, Hardegen NJ and Aggarwal BB. . 1998 Biochem. Pharmacol. 55: 775–783.

  • Kutchera W, Jones DA, Matsunami N, Groden J, McIntyre TM, Zimmerman GA, White RL and Prescott SM. . 1996 Proc. Natl. Acad. Sci. USA 93: 4816–4820.

  • Malinin NL, Boldin MP, Kovalenko AV and Wallach D. . 1997 Nature 385: 540–544.

  • Morteau JO, Han DS and Balfour Sartor R. . 1998 Immunology 95: 537–543.

  • Natarajan K, Sanjaya S, Burke Jr TR, Grunberger D and Aggarwal BB. . 1996 Proc. Natl. Acad. Sci. USA 93: 9090–9095.

  • Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P, Markham A, Krush AJ, Peterson G, Hamilton SR, Nilbert MC, Levy DB, Bryan TM, Preisinger AM, Smith KJ, Su L-K, Kinzler KW and Vogelstein B. . 1991 Science 253: 665–669.

  • Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, Traskos M, Evans JF and Taketo MM. . 1996 Cell 87: 803–809.

  • Pereira MA, Grubbs CJ, Barnes LH, Li H, Olson GR, Eto I, Juliana M, Whitaker LM, Kelloff GJ, Steele VE and Lubet RA. . 1996 Carcinogenesis 17: 1305–1311.

  • Plummer SM and Faux SP. . 1994 Carcinogenesis 15: 449–453.

  • Powell SM, Zilz N, Beazer-Barclay Y, Bryan M, Hamilton SR, Thibodeau SN, Vogelstein B and Kinzler KW. . 1992 Nature 359: 235–237.

  • Rao VV, Simi B and Reddy BS. . 1993 Carcinogenesis 14: 2219–2225.

  • Rosenberg L, Palmer JR, Zauber AG, Warshauer ME, Stolley PD and Shapiro S. . 1991 J. Natl. Cancer. Inst. 83: 355–358.

  • Samaha HS, Kellof GJ, Steele V, Rao CV and Reddy BS. . 1997 Cancer Res. 57: 1301–1305.

  • Sanjaya S and Aggarwal BB. . 1995 J. Biol. Chem. 270: 24995–25000.

  • Schiffman MH, Andrews AW, Daniels J, Robinson A, Smith L, Nair PP and Wilkins TD. . 1989 Mutat. Res. 222: 351–357.

  • Schmedtje JF, Yan-Shan J, Lui W-L, Dubois RN and Runge MS. . 1997 J. Biol. Chem. 272: 601–608.

  • Scudiero DA, Shoemaker RH, Paull KD, Monks A, Tierney S, Nofziger TH, Currens MJ, Seriff D and Boyd MR. . 1988 Cancer Res. 48: 4827–4833.

  • Srivastava R and Srimal RC. . 1985 Indian J. Med. Res. 81: 215–223.

  • Subbaramaiah K, Chung WJ, Michaluart P, Telang N, Tanabe T, Inoue H, Jang M, Pezzuto JM and Dannenberg AJ. . 1998 J. Biol. Chem. 273: 21875–21882.

  • Subbaramaiah K, Zakim D, Weksler BB and Dannenberg AJ. . 1997 Proc. Soc. Exp. Biol. Med. 216: 201–210.

  • Thun MJ, Nanboordiri MM and Heath CW. . 1991 New Eng. J. Med. 325: 1593–1596.

  • Tordman C, Coge F, Andre N, Rique H, Spedding M and Bonnet J. . 1995 Biochem. Biophys. Acta 1256: 249–256.

  • Trujillo MA, Garewal HS and Sampliner RE. . 1994 Digest. Diseases Sci. 39: 2260–2266.

  • Tsujii M and Dubois RN. . 1995 Cell 83: 493–501.

  • Vainio H. . 1997 Non-steroidal Anti-inflammatory Drugs, IARC Handbooks of Cancer Prevention Volume 1 Lyon: IARC press.

    Google Scholar 

  • Vane JR and Botting RM. . 1995 Inflammation Res. 44: 1–10.

  • Woronicz JD, Gao X, Cao Z, Rothe M and Goeddel DV. . 1997 Science 278: 866–869.

  • Xie W and Herschman HR. . 1995 J. Biol. Chem. 270: 27622–27628.

  • Yin MJ, Yamamoto Y and Gaynor RB. . 1998 Nature 396: 77–80

  • Zarcovic M, Qin X, Nakatsuru Y, Oda H, Nakamura T, Shamsuddin AM and Ishikawa T. . 1993 Carcinogenesis 14: 1261–1264.

  • Zeng-gang L, Hsu H, Goeddel DV and Karin M. . 1996 Cell 87: 565–576.

Download references

Acknowledgements

We thank Helen Ball for technical assistance and also Andreas Gescher and Ann Hudson for helpful discussions and comments on the manuscript. SM Plummer benefited from a BACR mid-career fellowship which supported part of this work.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Plummer, S., Holloway, K., Manson, M. et al. Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-κB activation via the NIK/IKK signalling complex. Oncogene 18, 6013–6020 (1999). https://doi.org/10.1038/sj.onc.1202980

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202980

Keywords

This article is cited by

Search

Quick links