Abstract
Increased expressions of cyclooxygenase-2 (COX-2) and its downstream metabolite, prostaglandin E2 (PGE2), are well documented events in the development of colorectal cancer. Interestingly, PGE2 itself can induce the expression of COX-2 thereby creating the potential for positive feedback. Although evidence for such a positive feedback has been previously described, the specific E-type prostanoid (EP) receptor subtype that mediates this response, as well as the relevant signaling pathways, remain unclear. We now report that the PGE2 stimulated induction of COX-2 expression in human colon cancer HCA-7 cells is mediated by activation of the prostanoid EP4 receptor subtype and is followed by coupling of the receptor to Gαi and the activation of phosphatidylinositol 3-kinase. Subsequent activation of metalloproteinases releases membrane bound heparin-binding epidermal growth factor-like growth factor resulting in the transactivation of epidermal growth factor receptors and the activation of the extracellular signal-regulated kinases and induction of COX-2 expression. This induction of COX-2 expression by PGE2 stimulation of the prostanoid EP4 receptor may underlie the upregulation of COX-2 during colorectal cancer and appears to be an early event in the process of tumorigenesis.
Original language | English (US) |
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Pages (from-to) | 408-417 |
Number of pages | 10 |
Journal | European Journal of Pharmacology |
Volume | 718 |
Issue number | 1-3 |
DOIs | |
State | Published - 2013 |
Keywords
- Colon cancer
- Cyclooxygenase-2
- G
- Human prostanoid EP4 receptor
- PGE
- Phosphatidylinositol 3-kinase
- Prostaglandin E
ASJC Scopus subject areas
- Pharmacology