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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Johansson C. & Bergstrom S. Prostaglandins and protection of the gastrointestinal mucosa. Scand. J. Gastroenterol. S77, 21–46 (1982).
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).
Johansson, C. et al. Trophic actions of oral E2 prostaglandins on the rat gastrointestinal mucosa. Adv. Prostaglandin Thromboxane Leukot. Res. 12, 403–407 (1983).
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).
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).
Levy, G.N. Prostaglandin H synthases, nonsteroidal anti-inflammatory drugs, and colon cancer. FASEB. J. 11, 234–247 (1997).
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).
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).
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).
Narumiya, S., Sugimoto, Y. & Ushikubi, F. Prostanoid receptors, structures, properties, and functions. Physiol. Rev. 79, 1193–1226 (1999).
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).
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).
Prenzel, N. et al. EGF receptor transactivation by G-protein-coupled receptors require metalloproteinase cleavage of proHB-EGF. Nature 402, 884–888 (1999).
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).
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).
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).
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).
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).
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).
Dubois, R.N. & Smalley, W.E. Cyclooxygenase, NSAIDs, and colorectal cancer. J. Gastroenterology 6, 898–906 (1996).
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)
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).
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).
Baselga, J. Monoclonal antibodies directed at growth factor receptors. Ann. Oncol. 11, 187–190 (2000).
Torrance, C.J. et al. Combinatorial chemoprevention of intestinal neoplasia. Nature Med. 6, 1024–1028 (2000).
Kobayashi, I. et al. A cell line derived form normal gastric mucosa of rat. In Vitro Cell Dev. Biol. Anim. 32, 259–261 (1996).
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
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights 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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm0302-289
This article is cited by
-
COX 2-inhibitors; a thorough and updated survey into combinational therapies in cancers
Medical Oncology (2024)
-
Key regulator PNPLA8 drives phospholipid reprogramming induced proliferation and migration in triple-negative breast cancer
Breast Cancer Research (2023)
-
Cyclooxygenase-2 activates EGFR–ERK1/2 pathway via PGE2-mediated ADAM-17 signaling in testosterone-induced benign prostatic hyperplasia
Inflammopharmacology (2023)
-
A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors
Nature Cancer (2023)
-
Pou3f1 mediates the effect of Nfatc3 on ulcerative colitis-associated colorectal cancer by regulating inflammation
Cellular & Molecular Biology Letters (2022)