Cyclooxygenase-2 transactivates the epidermal growth factor receptor through specific E-prostanoid receptors and Tumor Necrosis Factor-α converting enzyme

Abstract

Cyclooxygenase-2 is often highly expressed in epithelial malignancies and likely has an active role in tumor development. But how it promotes tumorigenesis is not clearly defined. Recent evidence suggests that this may involve transactivation of the epidermal growth factor receptor through Eprostanoid receptors, but reports differ about the mechanism by which this occurs. We found that Eprostanoid receptors 2-4, but not 1, transactivated the epidermal growth factor receptor. This required metalloproteinase activity, leading to release of growth factors from the cell surface. Both transforming growth factor-α and amphiregulin were released in response to overexpression of cyclooxygenase-2, but betacellulin and heparin-binding EGF-like growth factor were not. The metalloproteinase tumor necrosis factor-α converting enzyme was required for proteolytic release of transforming growth factor-α. We also found that addition of epidermal growth factor receptor ligands to HEK293 cells induced cyclooxygenase-2 expression, suggesting that by activating epidermal growth factor receptor signaling, cyclooxygenase-2 potentially creates a self-perpetuating cycle of cell growth. Consistent with this, inhibition of cyclooxygenase-2 reduced growth of epidermal growth factor receptor overexpressing MCF-10A breast epithelial cells in threedimensional culture.

Inhibitory effects of omega-3 fatty acids on injury-induced epidermal growth factor receptor transactivation contribute to delayed wound healing

“…Multiple signaling pathways are known to modulate transactivation of EGFR. For example, PGE 2 mediates activation of MMPs, which cleave EGFR ligands from the plasma membrane (2,38,39). It is well established that DHA and EPA reduce production of PGE 2 (6,49), which could dampen transactivation of EGFR.…”

Transgenic expression of cyclooxygenase-2 in mouse intestine epithelium is insufficient to initiate tumorigenesis but promotes tumor progression

“…We and others have shown in vitro that PGE 2 transactivates EGFR [16–18], which is known to promote proliferation [18–21], survival [22,23], migration [17,19,24], and angiogenesis [25]. Collectively, these data led us to hypothesize that COX-2 might promote colorectal tumorigenesis by activating EGFR signaling.…”

Diacylglycerol kinase η modulates oncogenic properties of lung cancer cells

“…Cell proliferation was assessed by plating 10,000 cells in a 10-cm diameter plate, growing them in 1 % FBS with antibiotics for 5–7 days, and then counting the number of cells. Growth in soft agar was performed as described [13]. …”