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

Hsi-Hsien Hsu,Marthandam Shibu,Hui-Nung Shih,Vijaya Viswanadha,Chien-Chung Lin,Ray-Jade Chen,Chia-Yao Shen,Chih-Yang Huang,Shin-Yi Li,Yueh-Min Lin,Sheng-Huang Chang

doi:10.3390/ijms18061132

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.

Highlights

Colorectal carcinoma (CRC) is one of the most prevalent cancers worldwide [1,2] and is the second leading cause of cancer-related mortality in developed countries [3]
The expression of COX2 in LoVo cells was evaluated by immunoblot assay and was found to increase following treatment with prostaglandin E2 (PGE2) at various concentrations (0, 1, 5 and 10 μM) (Figure 1A)
Our experiments show that EP2 and EP4 were the major proteins involved in upregulating the PI3K/Akt pathway after PGE2 treatment, and this survival pathway can control the p-GSK3β/β-catenin pathway

Summary

Introduction

Colorectal carcinoma (CRC) is one of the most prevalent cancers worldwide [1,2] and is the second leading cause of cancer-related mortality in developed countries [3]. Degradation of the extracellular matrix (ECM) is closely associated with the development of malignant tumors. ECM degradation by extracellular proteinases accelerates the progress of tumor cell invasion and metastasis [6]. Upregulation of MMP-2 and MMP-9 has been shown to play a key role in the progression, invasion and metastasis of colorectal cancer in animal models and patients [10]. COX2 expression is markedly elevated in most human colorectal cancers [11]. Kirsten Ras (KRAS) induces HT29 cell proliferation through the expression of COX2, EP1/EP4, p-Akt and GSK3β and increases Tcf transcriptional factor activation [17]. The upregulation of COX expression by the Ras/PI3K/GSK3β/β-catenin pathway is potentially responsible for the PGE2-induced migration in the human colon cancer cell line LoVo [18]

Methods

Results

Conclusion