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


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.

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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.


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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.

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Correspondence to Andrzej S. Tarnawski.

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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).

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