PGE2 regulates pancreatic stellate cell activity via the EP4 receptor

Abstract

Objectives-Pancreatic stellate cells are source of dense fibrotic stroma, a constant pathological feature of chronic pancreatitis (CP) and pancreatic adenocarcinoma (PDAC). We observed correlation between levels of cyclooxygenase-2 (COX-2) and its product prostaglandin E2 (PGE 2 ) and the extent of pancreatic fibrosis. Aim of this study was to delineate the effects of PGE 2 on immortalized human pancreatic stellate cells (HPSC) and to identify the receptor involved. The authors have no any potential conflict of interest including any financial, personal, or other relationships with other people or organizations that could inappropriately influence this work. MethodsPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptPancreas. Author manuscript; available in PMC 2014 April 01. by LC/MS/MS. HPSC proliferation was assessed by MTS assay; migration by Boyden chamber assay and invasion using an invasion chamber. Transient silencing was obtained by siRNA.Results-HPSC express COX-2 and synthesize PGE 2 . PGE 2 stimulated HPSC proliferation, migration and invasion; stimulated expression of both ECM and MMP genes. HPSC expressed all four EP receptors. Only blocking the EP4 receptor resulted in abrogation of PGE 2 mediated HPSC activation. Specificity of EP4 for the effects of PGE 2 on stellate cells was confirmed using specific antagonists.Conclusion-Our data indicate that PGE 2 regulates PSC profibrotic activities via EP4 receptor thus suggesting EP4 receptor as useful therapeutic target for pancreatic cancer to reduce desmoplasia.

The Pharmacological and Physiological Role of Multidrug-Resistant Protein 4

“…It has been shown that PGE 2 can downregulate tumor immunity through inhibiting dendritic cell (DC) differentiation and switching the function of DCs from induction of immunity to T-cell tolerance (Chinen et al, 2011); inhibiting CD8 1 T-cell proliferation and activity (Ganapathy et al, 2000); the inhibition of mature B-cell proliferation and induction of immature B-cell apoptosis (Shimozato and Kincade, 1999); downregulation of antitumor TH1 cytokines and upregulation of immunosuppressive TH2 cytokines (Fabricius et al, 2010); and inducing myeloid-derived suppressor cell differentiation (Sinha et al, 2007). More importantly, PGE 2 can bind to the EP2/4 receptor and activate the downstream cascades, leading to epithelium stem cell transition, metastasis, antiapoptosis, and proliferation (Rao et al, 2007;Rasmuson et al, 2012;Charo et al, 2013). PGE 2 induces the proliferation of colon and lung cancer cells by activating Ras-ERK and glycogen Fig.…”