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Angiotensin II and epidermal growth factor induce cyclooxygenase-2 expression in intestinal epithelial cells through
Lee W Slice1, Terence Chiu, Enrique Rozengurt
1Department of Medicine, David Geffen School of Medicine at UCLA, the CURE: Digestive Diseases Research Center, the Jonnson Comprehensive Cancer Center, University of California, Los Angeles 90095-1786, USA. lslice@mednet.ucla.edu
Abstract:
Colorectal carcinogenesis is a multistep process involving genetic mutations and alterations in rigorously controlled signaling pathways and gene expression that control intestinal epithelial cell proliferation, differentiation, and apoptosis. Cyclooxygenase-2 (COX-2) is aberrantly expressed in premalignant adenomatous polyps and colorectal carcinomas and is associated with increased epithelial cell proliferation, decreased apoptosis, and increased cell invasiveness. Currently, knowledge of the regulation of expression of COX-2 by endogenous cell-surface receptors is inadequate. Recently, in a non-transformed rat intestinal epithelial cell line (IEC-18), we showed induction of cell proliferation and DNA synthesis by angiotensin II (Ang II) via the endogenous Ang II type 1 receptor (Chiu, T., Santiskulvong, C., and Rozengurt, E. (2003) Am. J. Physiol. 285, G1-G11). We report that Ang II potently stimulated expression of COX-2 mRNA and protein as an immediate-early gene response through the Ang II type 1 receptor, correlating with an increase in prostaglandin I2 production. Ang II induced Cdc42 activation and filopodial formation. COX-2 expression was induced by epidermal growth factor (EGF), which activated Rac with lamellipodial formation. Inhibition of small GTPases by Clostridium difficile toxin B blocked COX-2 expression by Ang II and EGF. Inhibition of ERK activation by U0126 or PD98059 significantly decreased EGF-dependent COX-2 expression, but did not affect Ang II-dependent COX-2 expression. Conversely, inhibition of p38MAPK by SB202190 or PD169316 inhibited COX-2 expression by Ang II, but did not block COX-2 induction by EGF. Ang II caused Ca2+ mobilization. Inhibition of Ca2+ signaling by 2-aminobiphenyl borate blocked Ang II-dependent COX-2 expression. EGF did not induce Ca2+ mobilization, and 2-aminobiphenyl borate did not inhibit EGF-dependent COX-2 expression. Inhibition of COX-2 expression correlated with inhibition of prostaglandin I2 production. Luciferase promoter assays showed that Ang II-dependent transcriptional activation of the COX-2 promoter was dependent on activation of small GTPases and p38(MAPK) and on Ca2+ signaling via the cAMP-responsive element/activating transcription factor cis-acting element.
Insights
Angiotensin II (Ang II) and epidermal growth factor (EGF) stimulate cyclooxygenase-2 (COX-2) expression in intestinal cells via distinct signaling pathways. Ang II uses p38MAPK and Ca2+ signaling, while EGF relies on ERK, both involving small GTPases.
Area of Science:
- Molecular biology
- Cell signaling
- Gastroenterology
Background:
- Colorectal carcinogenesis involves genetic mutations and altered signaling pathways controlling cell proliferation, differentiation, and apoptosis.
- Cyclooxygenase-2 (COX-2) is upregulated in colorectal tumors, promoting proliferation, inhibiting apoptosis, and increasing invasiveness.
- Regulation of COX-2 expression by endogenous cell-surface receptors is not fully understood.
Purpose of the Study:
- To investigate the signaling mechanisms by which angiotensin II (Ang II) and epidermal growth factor (EGF) regulate cyclooxygenase-2 (COX-2) expression in intestinal epithelial cells.
- To elucidate the roles of small GTPases, MAP kinases, and calcium signaling in Ang II- and EGF-induced COX-2 expression.
Main Methods:
- Used a rat intestinal epithelial cell line (IEC-18).
- Stimulated cells with Ang II and EGF, then measured COX-2 mRNA and protein expression.
- Employed inhibitors for specific signaling pathways (small GTPases, ERK, p38MAPK, Ca2+ signaling) and performed luciferase promoter assays.
Main Results:
- Ang II potently stimulated COX-2 expression via the Ang II type 1 receptor, increasing prostaglandin I2 production.
- EGF also induced COX-2 expression.
- Ang II-induced COX-2 expression involved Cdc42 activation, p38MAPK, and Ca2+ mobilization.
- EGF-induced COX-2 expression involved Rac activation and ERK activation.
- Inhibition of small GTPases blocked COX-2 induction by both Ang II and EGF.
- Specific inhibitors differentiated the signaling pathways: p38MAPK and Ca2+ for Ang II; ERK for EGF.
Conclusions:
- Ang II and EGF differentially regulate COX-2 expression in intestinal epithelial cells through distinct signaling cascades.
- Ang II-dependent COX-2 induction relies on small GTPases, p38MAPK, and Ca2+ signaling.
- EGF-dependent COX-2 induction involves small GTPases and ERK signaling.
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