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.

Prostaglandin E2 transactivates EGF receptor: A novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy

Abstract

Prostaglandins (PGs), bioactive lipid molecules produced by cyclooxygenase enzymes (COX-1 and COX-2), have diverse biological activities, including growth-promoting actions on gastrointestinal mucosa1,2,3,4,5. They are also implicated in the growth of colonic polyps and cancers6. However, the precise mechanisms of these trophic actions of PGs remain unclear. As activation of the epidermal growth factor receptor (EGFR) triggers mitogenic signaling in gastrointestinal mucosa, and its expression is also upregulated in colonic cancers and most neoplasms7,8,9, we investigated whether PGs transactivate EGFR. Here we provide evidence that prostaglandin E2 (PGE2) rapidly phosphorylates EGFR and triggers the extracellular signal-regulated kinase 2 (ERK2)–mitogenic signaling pathway in normal gastric epithelial (RGM1) and colon cancer (Caco-2, LoVo and HT-29) cell lines. Inactivation of EGFR kinase with selective inhibitors significantly reduces PGE2-induced ERK2 activation, c-fos mRNA expression and cell proliferation. Inhibition of matrix metalloproteinases (MMPs), transforming growth factor-α (TGF-α) or c-Src blocked PGE2-mediated EGFR transactivation and downstream signaling indicating that PGE2-induced EGFR transactivation involves signaling transduced via TGF-α, an EGFR ligand, likely released by c-Src-activated MMP(s). Our findings that PGE2 transactivates EGFR reveal a previously unknown mechanism by which PGE2 mediates trophic actions resulting in gastric and intestinal hypertrophy as well as growth of colonic polyps and cancers.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: PGE2 transactivates EGFR and triggers mitogenic ERK2 signaling pathway in RGM-1 and Caco-2 cells.
Figure 2: Neutralizing antibody against the extracellular domain of EGFR inhibits PGE2-mediated EGFR transactivation and ERK2 signaling, and this action involves activation of matrix metalloproteinase(s) (MMP) and release of the EGFR ligand, TGF-α.
Figure 3: PGE2 mediates EGFR transactivation via intracellular c-Src. RGM1 cells and Caco-2 cells were pretreated with either vehicle, PGE2 or PP2 + PGE2.

References

  1. Johansson C. & Bergstrom S. Prostaglandins and protection of the gastrointestinal mucosa. Scand. J. Gastroenterol. S77, 21–46 (1982).

    Google Scholar 

  2. Reinhart, W.H., Muller, O. & Halter, F. Influence of long-term 16,16-dimethyl prostaglandin E2 treatment on the rat gastrointestinal mucosa. Gastroenterology 85, 1003–1010 (1983).

    CAS  PubMed  Google Scholar 

  3. Johansson, C. et al. Trophic actions of oral E2 prostaglandins on the rat gastrointestinal mucosa. Adv. Prostaglandin Thromboxane Leukot. Res. 12, 403–407 (1983).

    CAS  PubMed  Google Scholar 

  4. Dembinski, A. & Konturek, S.J. Effects of E, F, and I series prostaglandins and analogues on growth of gastroduodenal mucosa and pancreas. Am. J. Physiol 248, G170–175 (1985).

    Article  Google Scholar 

  5. Sheng, H., Shao, J., Washington, M.K. & DuBois R.N. Prostaglandin E2 increases growth and motility of colorectal carcinoma cells. J. Biol. Chem. 276, 18075–18081 (2001).

    CAS  Article  Google Scholar 

  6. Levy, G.N. Prostaglandin H synthases, nonsteroidal anti-inflammatory drugs, and colon cancer. FASEB. J. 11, 234–247 (1997).

    CAS  Article  Google Scholar 

  7. Resnick, M.B., Gallinger, S., Wang, H.H. & Odze, R.D. Growth factor expression and proliferation kinetics in periampullary neoplasms in familial adenomatous polyposis. Cancer 76, 187–194 (1995).

    CAS  Article  Google Scholar 

  8. Shimada, N. et al. A comparative study of nucleolar organizer region, proliferating cell nuclear antigen and epidermal growth factor receptor staining in colon tumors. J. Gastroenterol. Hepatol. 13, 794–800 (1998).

    CAS  Article  Google Scholar 

  9. Malecka-Panas, E. et al. Differential activation of total and EGF receptor (EGFR) tyrosine kinase (tyr-k) in the rectal mucosa in patients with adenomatous polyps, ulcerative colitis and colon cancer. Hepatogastroenterology 44, 435–440 (1997).

    CAS  PubMed  Google Scholar 

  10. Narumiya, S., Sugimoto, Y. & Ushikubi, F. Prostanoid receptors, structures, properties, and functions. Physiol. Rev. 79, 1193–1226 (1999).

    CAS  Article  Google Scholar 

  11. Hackel, P.O., Zwick, E., Prenzel, N. & Ullrich, A. Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr. Opin. Cell Biol. 11, 184–189 (1999).

    CAS  Article  Google Scholar 

  12. Luttrell, L.M., Daaka, Y. & Lefkowitz, R.J. Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Curr. Opin. Cell Biol. 11, 177–183 (1999).

    CAS  Article  Google Scholar 

  13. Prenzel, N. et al. EGF receptor transactivation by G-protein-coupled receptors require metalloproteinase cleavage of proHB-EGF. Nature 402, 884–888 (1999).

    CAS  Article  Google Scholar 

  14. Eguchi, S., Dempsey, P.J., Frank, G.D., Motley, ED. & Ingami, T. Activation of MAPKs by angiotensin II in vascular smooth muscle cell. Metalloprotease-dependent EGF receptor activation is required for activation of ERK and p38 MAPK but not for JNK. J. Biol. Chem. 276, 7957–7962 (2001).

    CAS  Article  Google Scholar 

  15. Callejas, N.A., Casado, M., Diaz-Guerra, M.J.M., Bosca, L. & Martin-Sanz, P. Expression of cyclooxygenase-2 promotes the release of matrix metalloproteinase-2 and –9 in fetal rat hepatocytes. Hepatology 33, 860–867 (2001).

    CAS  Article  Google Scholar 

  16. Prenzel, N., Fischer, O.M., Streit, S., Hart, S. & Ullrich, A. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr. Relat. Cancer 8, 11–31 (2001).

    CAS  Article  Google Scholar 

  17. Younes, N., Fernandez, L. & Lechago, J. Transforming growth factor α (TGFα) expression in biopsies of colorectal carcinoma is a significant prognostic indicator. Anticancer Res. 16, 1999–2004 (1996).

    CAS  PubMed  Google Scholar 

  18. Moskal, T.L., Huang, S., Ellis, L.M., Fristsche, H.A. Jr & Chakrabarty, S. Serum levels of transforming growth factor α in gastrointestinal cancer patients. Cancer Epidemiol. Biomarkers Prev. 4, 127–131 (1995).

    CAS  PubMed  Google Scholar 

  19. Barnes, C.J. et al. Effect of aspirin on prostaglandin E2 formation and transforming growth factor α expression in human rectal mucosa from individuals with a history of adenomatous polyps of the colon. Cancer Epidemiol. Biomark. Prev. 8, 311–315 (1999).

    CAS  Google Scholar 

  20. Dubois, R.N. & Smalley, W.E. Cyclooxygenase, NSAIDs, and colorectal cancer. J. Gastroenterology 6, 898–906 (1996).

    Article  Google Scholar 

  21. Yang, V.W. et al. Tissue prostanoids as biomarkers for chemoprevention of colorectal neoplasia: Correlation between prostanoid synthesis and clinical response in familial adenomatous polyposis. Prostaglandins Other Lipid Mediat. 60, 83–96 (2000)

    CAS  Article  Google Scholar 

  22. Oshima, M. et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87, 803–809 (1996).

    CAS  Article  Google Scholar 

  23. Kinoshita, T. et al. Growth stimulation and induction of epidermal growth factor receptor by overexpression of cyclooxygenases 1 and 2 in human colon carcinoma cells. Biochim. Biophys. Acta 1438, 120–30 (1999).

    CAS  Article  Google Scholar 

  24. Baselga, J. Monoclonal antibodies directed at growth factor receptors. Ann. Oncol. 11, 187–190 (2000).

    PubMed  Google Scholar 

  25. Torrance, C.J. et al. Combinatorial chemoprevention of intestinal neoplasia. Nature Med. 6, 1024–1028 (2000).

    CAS  Article  Google Scholar 

  26. Kobayashi, I. et al. A cell line derived form normal gastric mucosa of rat. In Vitro Cell Dev. Biol. Anim. 32, 259–261 (1996).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors thank K. Tsugawa for technical assistance and M.K. Jones for helpful discussions. This work was supported by the Department of Veterans Affairs Medical Research Service Merit Review, Research Enhancement Awards and the Minority Initiative to A.S.T.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andrzej S. Tarnawski.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pai, R., Soreghan, B., Szabo, I. et al. Prostaglandin E2 transactivates EGF receptor: A novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med 8, 289–293 (2002). https://doi.org/10.1038/nm0302-289

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0302-289

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing