Transcriptional Regulation of Δ6-Desaturase by Peroxisome Proliferative-Activated ReceptorδAgonist in Human Pancreatic Cancer Cells: Role of MEK/ERK1/2 Pathway

Maryam Darabi,Shima Byagowi,Shahab Mirshahvaladi,Masoud Darabi,Shabnam Fayezi,Mehdi Sahmani

doi:10.1155/2013/607524

Abstract

The Δ6-desaturase (Δ6D), also known as fatty acid desaturase 2, is a regulatory enzyme in de novo fatty acid synthesis, which has been linked to obesity and diabetes. The aim of the present study was to investigate the effect of peroxisome proliferative-activated receptor δ (PPARδ) agonist and MEK/ERK1/2-dependent pathway on the expression of Δ6D in human pancreatic carcinoma cell line PANC-1. PANC-1 cells cultured in RPMI-1640 were exposed to the commonly used ERK1/2 pathway inhibitor PD98059 and PPARδ agonist GW0742. Changes in mRNA and protein expression of Δ6D were then determined using real-time RT-PCR and Western blot, respectively. The expression of Δ6D (P < 0.01) increased following treatment with PPARδ agonist both at mRNA and protein levels, whereas no significant change was observed after treatment with MEK/ERK1/2 pathway inhibitor. It was also found that the increase in the expression of Δ6D in response to GW0742 was significantly inhibited by PD98059 (>40%, P < 0.05) or EGF receptor-selective inhibitor AG1478 (>25%, P < 0.05) pretreatment. PPARδ and MEK/ERK1/2 signaling pathways affect differentially the expression of Δ6D in pancreatic cancer cells. Furthermore, there may be an inhibitory crosstalk between these two regulatory pathways on the mRNA expression of Δ6D and subsequently on Δ6D protein expression.

Highlights

Numerous in vitro and in vivo studies indicate the critical role of fatty acids in cell membrane fluidity, which in turn affect ligand binding and cellular signal transduction of surface receptors and G-proteins [1,2,3]
To define if there is a connection between peroxisome proliferative-activated receptor δ (PPARδ) and ERK1/2 mitogen-activated protein kinase (MAPK) signaling pathway on the expression of Δ6 fatty acid desaturase (Δ6D) enzyme, PANC-1 cells were treated with a specific PPARδ agonist (GW0742), a selective inhibitor of MAP kinase (PD98059), or a EGF receptor-selective tyrosine kinase inhibitor (AG1478)
It was found that the increase in expression of Δ6D in response to the PPARδ agonist was significantly inhibited (>40%, P = 0.032) by PD98059 pretreatment

Summary

Introduction

Numerous in vitro and in vivo studies indicate the critical role of fatty acids in cell membrane fluidity, which in turn affect ligand binding and cellular signal transduction of surface receptors and G-proteins [1,2,3]. This role has been demonstrated by the fact that the altered levels of fatty acid desaturase enzymes are associated with various human diseases like diabetes and atherosclerosis [4, 5]. FADS2deficient mouse model has revealed that Δ6D is the main enzyme in in vivo production of n-6 polyunsaturated fatty acids (PUFA) [10]

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Results

Conclusion