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 mucosa(1-5). They are also implicated in the growth of colonic polyps and cancers(6). 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 neoplasms(7-9), we investigated whether PGs transactivate EGFR. Here we provide evidence that prostaglandin E-2 (PGE(2)) 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 PGE(2)-induced ERK2 activation, c-fos mRNA expression and cell proliferation. Inhibition of matrix metalloproteinases (MMPs), transforming growth factor-alpha (TGF-alpha) or c-Src blocked PGE(2)-mediated EGFR transactivation and downstream signaling indicating that PGE(2)-induced EGFR transactivation involves signaling transduced via TGF-alpha, an EGFR ligand, likely released by c-Src-activated MMP(s). Our findings that PGE(2) transactivates EGFR reveal a previously unknown mechanism by which PGE(2) mediates trophic actions resulting in gastric and intestinal hypertrophy as well as growth of colonic polyps and cancers.