Gastrin and EGF synergistically induce cyclooxygenase‐2 expression in Swiss 3T3 fibroblasts that express the CCK₂ receptor

Abstract

Over-expression of cyclooxygenase-2 (COX-2) has been demonstrated to be tumorigenic in transgenic mice. Chronic treatment with NSAIDs is chemoprotective for colorectal cancer. Gastrin is a growth factor for gastric mucosa and has been shown to promote proliferation of colorectal cells. Recent studies suggest that COX-2 expression levels could mediate the growth effects of gastrin. Here, we report that gastrin increased PGE2 secretion in Swiss 3T3 cells expressing the CCK2 receptor. Gastrin dose dependently induced COX-2 protein levels in a time dependent manner. COX-2 mRNA levels were rapidly induced by a dose dependent increase in gastrin. Prior treatment of the cells with the CCK2 receptor specific antagonist, L365,260, inhibited gastrin-induced COX-2 protein and mRNA expression. Pretreatment with L364,714, the CCK1 receptor specific antagonist did not block COX-2 induction by gastrin. Inhibition of de novo protein synthesis by cycloheximide did not block COX-2 mRNA induction by gastrin. Also, gastrin-dependent COX-2 expression did not require PKC activity, activation of ERK, or transactivation of EGFR. However, co-stimulation with EGF and gastrin synergistically induced COX-2 protein and mRNA expression and PGE2 secretion. Measurements of COX-2 mRNA stability and COX-2 gene transcription reveal that EGF significantly increased the half-life of COX-2 mRNA with only a slight increase in the COX-2 transcription rate. Conversely, gastrin significantly increased COX-2 gene transcription rates but did not enhance COX-2 mRNA stability.

Plasminogen activator inhibitor 1: Mechanisms of its synergistic regulation by growth factors

“…A similar effect of EGF has also been found on mRNA of other genes, including Cox2 (Slice, Hodikian et al 2003), TβRII (Song, Krebs et al 2006), EGFR ), IL-1alpha, IL-1beta and IL-6 , p21/CIP1 . TGFα, which also binds to EGFR, substitute for EGF in mRNA stabilization McCulloch, Walker et al 1998).…”

Cholecystokinin and Gastrin Receptors

“…In several cellular models such as gastric and colonic cancer cells, intestinal epithelial cells and fibroblasts transfected with the CCK2R, gastrin has been shown to enhance cyclooxygenase-2 (COX-2) gene expression (100,191,482). This key enzyme of prostaglandin synthesis is known to play an important role in inflammation processes and carcinogenesis.…”

Gastrin Enhances the Angiogenic Potential of Endothelial Cells via Modulation of Heparin-Binding Epidermal-Like Growth Factor

“…[10][11][12], and matrix metalloproteinase (MMP) enzymes (13)(14)(15). Importantly, much emphasis has been placed on the ability of gastrin to both up-regulate ligands of the epidermal growth factor (EGF) receptor, in particular amphiregulin and heparin-binding EGF-like growth factor (HB-EGF; refs.…”