Prostaglandin E2-Induced COX-2 Expressions via EP2 and EP4 Signaling Pathways in Human LoVo Colon Cancer Cells

Abstract

Metastasis is the most dangerous risk faced by patients with hereditary non-polyposis colon cancer (HNPCC). The expression of matrix metalloproteinases (MMPs) has been observed in several types of human cancers and regulates the efficacy of many therapies. Here, we show that treatment with various concentrations of prostaglandin E2 (PGE2; 0, 1, 5 or 10 μM) promotes the migration ability of the human LoVo colon cancer cell line. As demonstrated by mRNA and protein expression analyses, EP2 and EP4 are the major PGE2 receptors expressed on the LoVo cell membrane. The Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt cell survival pathway was upregulated by EP2 and EP4 activation. Following the activation of the PI3K/Akt pathway, β-catenin translocated into the nucleus and triggered COX2 transcription via LEF-1 and TCF-4 and its subsequent translation. COX2 expression correlated with the elevation in the migration ability of LoVo cells. The experimental evidence shows a possible mechanism by which PGE2 induces cancer cell migration and further suggests PGE2 to be a potential therapeutic target in colon cancer metastasis. On inhibition of PGE2, in order to determine the downstream pathway, the levels of PI3K/Akt pathway were suppressed and the β-catenin expression was also modulated. Inhibition of EP2 and EP4 shows that PGE2 induces protein expression of COX-2 through EP2 and EP4 receptors in LoVo colon cancer cells.

Evaluation of Microglia/Macrophage Cells from Rat Striatum and Prefrontal Cortex Reveals Differential Expression of Inflammatory-Related mRNA after Methamphetamine

“…Thus, high doses of METH may promote PGE2 production in brain microglia that exacerbates LPS-induced IL1β production. The enhanced expression of Ptger2 suggested by our current RNAseq data could further promote this cycle by allowing PGE2 to act in an autocrine fashion to induce COX2 expression via EP2 receptor activation [60]. This feed-forward cycle involving LPS, EP2, and COX2 is supported by the observation that EP2-deficient mice have reduced serum levels of inflammatory mediators after the LPS challenge [61].…”

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

“…Prostaglandin E2 (PGE2) receptor 2 subtype (EP2) is a G protein-coupled plasma membrane receptor for PGE2, which acts through numerous signaling pathways to regulate various physiological functions, including tumor occurrence, invasion and metastasis, angiogenesis, chronic inflammation, tumor immunity and cell apoptosis (1). Recently, various studies have focused on identifying the specific EP2 receptors and signaling pathways that regulate the pleiotropic activities of the cyclooxygenase-2 (cOX-2)/PGE2/EP2 pathway (2)(3)(4)(5).…”

Prostaglandin receptor EP2 is a novel molecular target for high-risk neuroblastoma

“…1A and 1B). PGE 2 has been reported to regulate tumorigenesis through all four EP receptors, among which the Gα s -coupled EP2 and EP4 receptors have been mostly studied for their potential roles in the development and progression of tumors including those of breast, colon, lung, ovary, prostate, skin, and stomach (67)(68)(69)(70)(71)(72)(73)(74). It appears that EP2 and EP4 receptors are ubiquitously present in most tumors and likely function synergistically to enhance cancer cell activities because both receptors in a very similar way can trigger cAMP signaling as well as G proteinindependent pathway (15,67).…”