Docosahexaenoic Acid Inhibits Tumor Promoter-Induced Urokinase-Type Plasminogen Activator Receptor by Suppressing PKCδ- and MAPKs-Mediated Pathways in ECV304 Human Endothelial Cells

Sen Lian,Yong Xia,Young Do Jung,Kyung Keun Kim,Hyun Joong Yoon,Trong Thuan Ung,Nam Ho Kim,Thi Thinh Nguyen,Aamir Ahmad

doi:10.1371/journal.pone.0163395

Abstract

The overexpression of urokinase-type plasminogen activator receptor (uPAR) is associated with inflammation and virtually all human cancers. Despite the fact that docosahexaenoic acid (DHA) has been reported to possess anti-inflammatory and anti-tumor properties, the negative regulation of uPAR by DHA is still undefined. Here, we investigated the effect of DHA on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced uPAR expression and the underlying molecular mechanisms in ECV304 human endothelial cells. DHA concentration-dependently inhibited TPA-induced uPAR. Specific inhibitors and mutagenesis studies showed that PKCδ, JNK1/2, Erk1/2, NF-κB, and AP-1 were critical for TPA-induced uPAR expression. Application of DHA suppressed TPA-induced translocation of PKCδ, activation of the JNK1/2 and Erk1/2 signaling pathways, and subsequent AP-1 and NF-κB transactivation. In conclusion, these observations suggest a novel role for DHA in reducing uPAR expression and cell invasion by inhibition of PKCδ, JNK1/2, and Erk1/2, and the reduction of AP-1 and NF-κB activation in ECV304 human endothelial cells.

Highlights

Tumor metastasis is the most common cause of poor prognosis and deaths in cancer patients
TPA-stimulated urokinase-type plasminogen activator receptor (uPAR) mRNA expression (Fig 1A), protein expression (Fig 1B), and promoter activity (Fig 1C) were inhibited by docosahexaenoic acid (DHA) in a concentration-dependent manner as illustrated. These results suggested that DHA inhibited TPA-induced uPAR expression in ECV304 cells
This illustrated that PKCδ activation is involved in TPA-induced uPAR, which was inhibited by the addition of DHA

Summary

Introduction

Tumor metastasis is the most common cause of poor prognosis and deaths in cancer patients. Urokinase-type plasminogen activator (uPA) and urokinase-type plasminogen activator receptor (uPAR) system is thought to play a role in tumor angiogenesis [1] and tumor metastasis [2]. UPAR is over-expressed in tumors by multiple tumor-associated cell types including the tumor cells themselves, stromal cells and endothelial cells [3]. Coordination of extracellular matrix proteolysis and cell signaling by uPAR underlies its important function in tumor. DHA Inhibits uPAR in ECV304 Cells and Engineering Education (www.nrf.re.kr). All above funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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