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 Paper
  • Published:

Nitric oxide upregulates the cyclooxygenase-2 expression through the cAMP-response element in its promoter in several cancer cell lines

Oncogene volume 24, pages 6689–6698 (2005)Cite this article

Abstract

We previously showed that nitric oxide (NO) induces overexpression of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 in cancer cells. Here, we investigated the mechanisms by which NO induces COX-2 expression in cancer cells. We found that the cAMP-response element (CRE) is a critical factor in NO-induced COX-2 expression in all cells tested. We found that in cancer cells, three transcription factors (TFs) – cAMP response element-binding protein (CREB), activating transcription factor-2 (ATF-2) and c-jun, bound the CRE in the COX-2 promoter, and their activities were increased by addition of the NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP). NO-induced activation of soluble guanylate cyclase (sGC), p38 and c-Jun NH2-terminal kinase (JNK) upregulated the three TFs, leading to COX-2 overexpression. Addition of dibutyryl-cGMP (db-cGMP) induced COX-2 expression in a manner similar to SNAP; this induction was blocked by a p38 inhibitor (SB202190), but not by a JNK inhibitor (SP600125). NO-induced cGMP was found to activate CREB and ATF-2 in a p38, but not c-jun-dependent manner, while NO induced JNK in a cGMP-independent manner, leading to subsequent activation of c-jun and ATF-2. These results suggest that the low concentrations of endogenous NO present in cancer cell may induce the expression of many genes, including COX-2, which promotes the growth and survival of tumor cells.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 4
Figure 5
Figure 3
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

Abbreviations

NO:

nitric oxide

iNOS:

inducible nitric oxide synthase

COX-2:

cyclooxygenase-2

CRE:

cAMP-response element

sGC:

soluble guanylate cyclase

PGE2:

prostaglandin E2

HNSCC:

head and neck squamous cell carcinoma

MAPK:

mitogen-activated protein kinase

ERK:

extracellular signal-regulated kinase

JNK:

c-Jun NH2-terminal kinase

CREB:

cAMP response element-binding protein

ATF-2:

activating transcription factor-2

AP-1:

activator protein-1

PKA:

cAMP-dependent protein kinase

PKC:

protein kinase-C

PKG:

protein kinase G

References

  • Bogdan C . (2001). Trends Cell Biol., 11, 66–75.

  • Browning DD, Mcshane MP, Marty C and Ye RD . (2000). J. Biol. Chem., 275, 2811–2816.

  • Chabot-Fletcher M . (1996). Pharmacol. Rev. Commun., 8, 317–324.

  • Chan G, Boyle JO, Yang EK, Zhang F, Sachs PG, Shah JP, Edelstein D, Soslow RA, Koki AT, Woerner BM, Masferrer JL and Dannenberg AJ . (1999). Cancer Res., 59, 991–994.

  • Chung PS, Rhee CK, Kim KH, Paek W, Chung J, Paiva MB, Eshraghi AA, Castro DJ and Saxton RE . (2000). Laryngoscope, 110, 1312–1316.

  • Coffery RJ, Hawkey CJ, Damstrup L, Graves-Deal R, Daniel VC, Dempsey PJ, Chinery R, Kirkland SC, DuBois RN, Jetton TL and Morrow JD . (1997). Proc. Natl. Acad. Sci. USA, 94, 657–662.

  • Gallo O, Masini E, Morbidelli L, Franchi A, Fini-Storchi I, Vergari WA and Ziche M . (1998). J. Natl. Cancer Inst., 90, 587–596.

  • Guo YS, Hellmich MR, Wen XD and Townsend Jr CM . (2001). J. Biol. Chem., 276, 22941–22947.

  • Habib A, Bernard C, Lebret M, Creminon C, Esposito B, Tedgui A and Maclouf J . (1997). J. Immunol., 158, 3845–3851.

  • Han JA, Kim JI, Ongusaha PP, Hwang DH, Ballou LR, Mahale A, Aaronson SA and Lee SW . (2002). EMBO J., 21, 5635–5644.

  • Heo DS, Snyderman C, Gollin SM, Pan S, Walker E, Deka R, Barnes EL, Johnson JT, Herberman RB and Whiteside TL . (1989). Cancer Res., 49, 5167–5175.

  • Howe LR, Crawford HC, Subbaramaiah K, Hassell JA, Dannenberg AJ and Brown AM . (2001). J. Biol. Chem., 276, 20108–20115.

  • Inoue H, Tanabe T and Umesono K . (2000). J. Biol. Chem., 275, 28028–28032.

  • Lee DW, Sung MW, Park SW, Seong WJ, Roh JL, Park BJ, Heo DS and Kim KH . (2002). Anticancer Res., 22, 2089–2096.

  • Liaudet L, Soriano FG and Szabo C . (2000). Crit. Care Med., 28 (Suppl), N37–N52.

  • Liu Y, Borchert GL and Phang JM . (2004). J. Biol. Chem., 279, 18694–18700.

  • Luque I and Gelinas C . (1997). Semin. Cancer Biol., 8, 103–111.

  • Nose F, Ichikawa T, Fujiwara M and Okayasu I . (2002). Am. J. Clin. Pathol., 117, 546–551.

  • Pai R, Soreghan B, Szabo IL, Pavelka M, Baatar D and Tarnawski AS . (2002). Nat. Med., 8, 289–293.

  • Park SW, Lee SG, Song SH, Heo DS, Park BJ, Lee DW, Kim KH and Sung MW . (2003). Int. J. Cancer, 107, 729–738.

  • Park YK, Nesterova M, Agrawal S and Cho-Chung YS . (1999). J. Biol. Chem., 274, 1573–1580.

  • Posadas I, Terencio MC, Guillen I, Ferrandiz ML, Coloma J, Paya M and Alcaraz MJ . (2000). Naunyn-Schied. Arch. Pharmacol., 361, 98–106.

  • Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG and Needleman P . (1993). Proc. Natl. Acad. Sci. USA, 90, 7240–7244.

  • Sheng H, Shao J, Washington MK and DuBois RN . (2001). J. Biol. Chem., 276, 18075–18081.

  • Slice LW, Bui L, Mak C and Walsh JH . (2000). Biochem. Biophys. Res. Commun., 276, 406–410.

  • Son HJ, Kim YH, Park DI, Kim JJ, Rhee PL, Paik SW, Choi KW, Song SY and Rhee JC . (2001). J. Clin. Gastroenterol., 33, 383–388.

  • Song SH, Jong HS, Choi HH, Inoue H, Tanabe T, Kim NK and Bang YJ . (2001). Cancer Res., 61, 4628–4635.

  • Stadler J, Harbrecht BG, DiSilvio M, Curran RD, Jordan ML, Simmons RL and Billiar TR . (1993). J. Leukocyte Biol., 53, 165–172.

  • Subbaramaiah K, Norton L, Gerald W and Dannenberg AJ . (2002). J. Biol. Chem., 277, 18649–18657.

  • Sun Y, Tang XM, Elizabeth HM, Kuo T and Sinicrope FA . (2002). Cancer Res., 62, 6323–6328.

  • Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK and Lee SS . (2001). Mutat. Res., 480–481, 243–268.

  • Tamura M, Sbastian S, Yang S, Gutates B, Ferrer K, Sasano H, Okamura K and Bulun SE . (2002). J. Biol. Chem., 277, 26208–26216.

  • Tanabe T and Tohnai N . (2002). Prostaglandins Other Lipid Mediators, 68–69, 95–114.

  • Tang Q, Chen W, Gonzales MS, Finch J, Inoue H and Bowden GT . (2001). Oncogene, 20, 5164–5172.

  • Tsai AL, Wei C and Kulmacz RJ . (1994). Arch. Biochem. Biophys., 313, 367–372.

  • Vadlamudi R, Mandal M, Adam L, Steinbach G, Mendelsohn J and Kumar R . (1999). Oncogene, 18, 305–314.

  • Wink DA, Vodovotz Y, Laval J, Laval F, Dewhirst MW and Mitchell JB . (1998). Carcinogenesis, 19, 711–721.

  • Xu XM, Tang JL, Chen X, Wang LH and Wu KK . (1997). J. Biol. Chem., 272, 6943–6950.

Download references

Acknowledgements

We thank Dr Lee Jung Weon (Cancer Research Institute, Seoul National University, Seoul, Korea) for helpful discussion. This work was supported in part by a Korea Research Foundation Grant (KRF-2002-041-E00134) and by BK21 project for Medicine, Dentistry and Pharmacy, Korea.

Author information

Authors and Affiliations

  1. Department of Tumor Biology, College of Medicine, Seoul National University, 28, Yongun-dong, Chongno-gu, Seoul, Korea

    Seok-Woo Park & Myung-Whun Sung

  2. Cancer Research Institute, College of Medicine, Seoul National University, 28, Yongun-dong, Chongno-gu, Seoul, Korea

    Seok-Woo Park, Myung-Whun Sung, Dae-Seog Heo & Seon-Hui Shim

  3. Department of Otorhinolaryngology – Head and Neck Surgery, College of Medicine, Seoul National University, 28, Yongun-dong, Chongno-gu, Seoul, Korea

    Myung-Whun Sung & Kwang-Hyun Kim

  4. Clinical Research Institute, College of Medicine, Seoul National University, 28, Yongun-dong, Chongno-gu, Seoul, Korea

    Myung-Whun Sung, Dae-Seog Heo & Kwang-Hyun Kim

  5. Department of Internal Medicine, College of Medicine, Seoul National University, 28, Yongun-dong, Chongno-gu, Seoul, Korea

    Dae-Seog Heo

  6. Department of Food Science and Nutrition, Nara Women's University, Nara, Japan

    Hiroyasu Inoue

Authors
  1. Seok-Woo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Myung-Whun Sung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dae-Seog Heo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroyasu Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seon-Hui Shim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kwang-Hyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Myung-Whun Sung.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, SW., Sung, MW., Heo, DS. et al. Nitric oxide upregulates the cyclooxygenase-2 expression through the cAMP-response element in its promoter in several cancer cell lines. Oncogene 24, 6689–6698 (2005). https://doi.org/10.1038/sj.onc.1208816

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208816

Keywords

This article is cited by

Search

Advanced search

Quick links