Prostaglandin E2 Increases Growth and Motility of Colorectal Carcinoma Cells

Abstract

Chronic use of nonsteroidal anti-inflammatory drugs results in a significant reduction of risk and mortality from colorectal cancer in humans. All of the mechanism(s) by which nonsteroidal anti-inflammatory drugs exert their protective effects are not completely understood, but they are known to inhibit cyclooxygenase activity. The cyclooxygenase enzymes catalyze a key reaction in the conversion of arachidonic acid to prostaglandins, such as prostaglandin E 2 (PGE 2 ). Here we demonstrate that PGE 2 treatment of LS-174 human colorectal carcinoma cells leads to increased motility and changes in cell shape. The prostaglandin EP 4 receptor signaling pathway appears to play a role in transducing signals which regulate these effects. PGE 2 treatment results in an activation of phosphatidylinositol 3-kinase/ protein kinase B pathway that is required for the PGE 2 -induced changes in carcinoma cell motility and colony morphology. Our results suggest that PGE 2 might enhance the invasive potential of colorectal carcinoma cells via activation of major intracellular signal transduction pathways not previously reported to be regulated by prostaglandins.There is a 40 -50% reduction in the relative risk of colorectal cancer and colorectal cancer-associated mortality in individuals taking nonsteroidal anti-inflammatory drugs (NSAIDs)

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

“…For example, Apc Δ716/+ mice had fewer gastrointestinal tumors when crossed with EP2 −/− mice [32] and EP2 was necessary for mammary hyperplasia in COX-2 transgenic mice [28]. To our knowledge, there are no reports suggesting that EP3 can transactivate EGFR, but EP4 has been shown to be involved in tumor cell motility [33] and it is over-expressed in tumors from Apc Δ716/+ mice [32]. None of these reports provided a direct link between EP2 or EP4 and EGFR, but combined with our data, they suggest that transactivation of EGFR through these EP receptors might have a role in development of breast and colon cancer and other malignancies.…”

The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells

“…PGE 2 signaling through the EP4 receptor has previously been associated with colorectal cancer. For example, PGE 2 has been reported to stimulate the proliferation and motility of LS174T colorectal cancer cells via EP4 dependent stimulation of PI-3-K/AKT signaling [10]. In addition Pozzi et al [36] demonstrated EP4 mediated PI-3-K/ ERK signaling pathway in mouse colon carcinoma cells.…”

“…PGE 2 treatment was shown to enhance incidence of colonic tumors in AOM-treated rats and attenuates non-steroidal anti-inflammatory drug (NSAID)-induced tumor regression in Apc Min/+ mice by increasing intestinal epithelial cell proliferation and reduction of apoptosis [7][8][9]. In addition, PGE 2 can increase cell survival, invasion, and migration of human colon cancer cells [10][11][12]. Collectively, these in vivo studies strongly implicated a role for elevated levels of PGE 2 in colorectal carcinogenesis.…”

“…PGE 2 stimulates the proliferation and motility of LS174T adenocarcinoma cells through the EP4 dependent activation of phosphatidylinositol 3-kinase/AKT signaling [10]. Furthermore, premalignant aberrant crypt foci formation in EP4 deficient mice following azoxymethane treatment is suppressed compared to the EP4 wildtype mice [15].…”

Activation of thromboxane receptor α induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells

“…This interest was sparked by the fact that COX inhibitors reduced the mortality rate from certain cancer patients [16,17] and that most of the tumors exhibited overexpression of COX-2, a potential oncogene [18]. One of the major COX-2 derived products, PGE 2 , has also been shown to induce the growth, migration, and invasiveness of carcinoma cells [19]. In view of the fact that PGE 2 up-regulates the expression of COX-2 in several cancer cell lines resulting in positive feedback actions of PGE 2 [20,21], we hypothesize that another COX-2 derived down-stream product with similar mitogenic activity, TXA 2 , will be also capable of inducing the expression of COX-2.…”