Suppression of Urokinase-Type Plasminogen Activator Receptor by Docosahexaenoic Acid Mediated by Heme Oxygenase-1 in 12-O-Tetradecanoylphorbol-13-Acetate-Induced Human Endothelial Cells.

Sen Lian,Young Do Jung,Shinan Li,Dhiraj Kumar Sah,Nam Ho Kim,Vinoth‐Kumar Lakshmanan

doi:10.3389/fphar.2020.577302

Abstract

Urokinase-type plasminogen activator receptor (uPAR) plays a crucial role in inflammation and tumor metastasis. Docosahexaenoic acid (DHA), a representative omega-3 polyunsaturated fatty acid, has been shown to exhibit anti-inflammatory and anti-tumor properties. However, the mechanism by which DHA negatively regulates uPAR expression is not yet understood. The aim of this study was to investigate the effect of DHA on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced uPAR expression and potential role of heme oxygenase-1 (HO-1) in DHA-induced inhibition of uPAR in human endothelial ECV304 cells. Results showed that TPA induced uPAR expression in a time dependent manner, while DHA inhibited uPAR expression in a concentration-dependent manner. Moreover, treatment with DHA induced HO-1 expression in a time- and concentration-dependent manner. In addition, DHA-induced inhibition of uPAR expression and cell invasion in TPA-stimulated cells was reversed by si-HO-1 RNA. Induction of HO-1 by ferric protoporphyrin IX (FePP) inhibited TPA-induced uPAR expression, and this effect was abolished by treatment with the HO-1 inhibitor tin protoporphyrin IX (SnPP). Additionally, carbon monoxide, an HO-1 product, attenuated TPA-induced uPAR expression and cell invasion. Collectively, these data suggest a novel role of DHA-induced HO-1 in reducing uPAR expression and cell invasion in human endothelial ECV304 cells.

Highlights

Cancer is among the leading causes of death in both economically developed and developing countries (Mathers et al, 2008)
We reported that Docosahexaenoic acid (DHA) suppressed Urokinase-type plasminogen activator receptor (uPAR) expression, and this effect was mediated by heme oxygenase-1 (HO-1) in human endothelial ECV304 cells
DHA did not significantly affect ECV304 cell viability. These results suggest that DHA inhibits TPAinduced uPAR expression in ECV304 cells at non-toxic concentrations

Summary

Introduction

Cancer is among the leading causes of death in both economically developed and developing countries (Mathers et al, 2008). Tumor metastasis is the leading cause of cancer-related mortality. UPAR has been shown to be involved in nearly every step of cancer metastasis, including cell migration (Schiller et al, 2009), adhesion (Andreasen et al, 1997; Liang et al, 2008), angiogenesis (Mignatti and Rifkin, 1995), and invasion (Subramanian et al, 2006; Kunigal et al, 2007). UPAR is thought to be an important regulator of the invasive properties of cancer cells (Blasi et al, 1987). Agents with the ability to block uPAR expression may serve as potential candidates for the treatment of human cancers. With respect to the anti-cancer effect, DHA treatment was reported to inhibit MMP-9 expression in human breast cancer cells, MCF-7 (Chen et al, 2013). DHA was shown to significantly decrease cytokine-induced adhesion molecule expression (Chen et al, 2003), diminish the adhesion of leukocytes to activated endothelial cells (Mayer et al, 2002), and to inhibit the production of cytokines by endothelial cells (Von Schacky, 2007)

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