Targeting Prostaglandin E EP Receptors to Inhibit Metastasis

Abstract

It is well established that high cyclooxygenase-2 (COX-2) expression contributes to the aggressive behavior of breast and other malignancies. Due to concerns regarding the safety of long-term use of COX-2 inhibitors as well as a desire to seek more effective alternatives to prevent and treat metastatic disease, we tested the hypothesis that inhibition of downstream signaling by the COX-2 product prostaglandin E 2 (PGE 2 ) would be as effective as inhibiting global prostaglandin synthesis. PGE 2 acts through four G-protein-coupled receptors designated EP1-4. Here, we summarize data from many laboratories regarding the role of individual E-series of prostaglandin (EP) receptors on cancer behavior and we discuss our own recent findings that antagonists of the PGE receptor subtype 4, EP4, inhibit experimental metastasis in a murine model of hormone-resistant, metastatic breast cancer. These initial results indicate that selective targeting of individual EP receptors should be investigated as an approach to exploit the high COX-2 activity in many epithelial malignancies. (Cancer Res 2006; 66(20): 9794-7) Cyclooxygenase-2 Is Highly Expressed in Breast CancerMany tumors and tumor cell lines, including breast, express elevated cyclooxygenase-2 (COX-2) protein levels that contribute to their malignant behavior (1). Epidemiologic studies indicate that chronic use of nonsteroidal anti-inflammatory drugs that inhibit Cox-mediated production of prostaglandins is associated with lower incidence of a number of tumor types, including breast cancers (2). In spite of recent advances in the treatment of hormone receptor-positive breast cancers, effective therapies are lacking for hormone-resistant and metastatic disease. Human breast cancers frequently have high PGE 2 levels and breast tumors with high COX-2 protein levels are more likely to metastasize (1).Protective effects of COX inhibitors both in preventing tumor induction and inhibiting growth of transplanted tumors are well established (3-5). Several mechanisms underlie these therapeutic effects. Direct effects of COX inhibitors on tumor cells have been shown, including inhibition of cancer cell proliferation and induction of apoptosis (6). Other studies support an indirect effect of COX inhibitors on tumor angiogenesis (4). COX inhibitors are also effective at limiting metastatic disease (3, 5). The antimetastatic effect depends on activation of natural killer (NK) cells (3, 7).The COX-2 Product Prostaglandin E 2 Acts through E-Series of Prostaglandin ReceptorsIn tumors, the principal COX-2 product is prostaglandin E 2 (PGE 2 ). Cellular effects of PGE 2 are mediated through a family of G-protein-coupled receptors designated EP1,2,3 and EP4 (8). Despite structural and sequence similarities among the four E-series of prostaglandin (EP) receptors, they are coupled to different intracellular signaling pathways. Ligand binding of EP1 is associated with phospholipase C activation and elevations in intracellular calcium, whereas EP2 and EP4 are coupled to protein kinase ...

Hepatitis B virus X protein promotes liver cell proliferation via a positive cascade loop involving arachidonic acid metabolism and p-ERK1/2

“…It has been reported that Gi/o proteins, which are known to affect a variety of cellular functions, activate p-ERK1/2 and subsequent cell proliferation signals [10,32]. AA metabolites are also able to induce cell growth and have been strongly implicated in tumor development [38,39]. Exogenous AA and its lipid metabolites have been shown to induce ERK activation [40].…”

Prostaglandins A1 and E1 influence gene expression in an established insect cell line (BCIRL-HzAM1 cells)

“…PGs also act in malignancy growth and metastasis. For example, EP4 signaling through phosphatidylinositol 3-kinase, Erk1 and Erk2 supports growth of CT26 colon carcinoma cells (Hull et al, 2004;Fulton et al, 2006). The potential influence of PGs on mammalian gene expression is emphasized by the revelation of a nuclear PG signaling system in which EP3 receptors are localized in the nuclear membrane.…”

Combinatorial intervention of prostaglandin E2 receptor and calcium sensing receptor to attenuate breast cancer cell proliferation, migration and bone metastasis

“…The treatment with non-steroidal antiinflammatory drugs (NSAIDs) that inhibit COX2 can reduce the risk and incidence of many types of cancer including breast cancer (13). However, in contrast to the serious potential cardiovascular complications of COX2 inhibitors, the direct inhibition of G-protein-linked prostaglandin E2 receptor (EP2) could serve as a much better alternative to COX2 inhibition as a means for breast cancer prevention and treatment (14,15). EP2 couples to Gα s and stimulates cyclic AMP (cAMP) accumulation, protein kinase A (PKA) activation and the phosphorylation of cAMP response element binding protein (CREB), as shown in Fig.…”

“…to address this question, one can use genetic, pharmacological and immunological approaches such as a) silence the expression of EP2 and CaR to analyze the compound knockdown by breast cancer cells, b) pharmacological inhibition of EP2 using EP2 antagonists and CaR inhibition by 'calcilytics' (15,(22)(23)(24)(25), and c) inhibition of EP2 and CaR by anti-EP2 and anti-CaR antibodies. The expression of CaR and EP2 can be decreased significantly by using short hairpin RNA (shRNA) in MDA-MB-231 cells.…”