Free Fatty Acid Receptor 4 (FFA4) Mediates the Inhibitory Effects of Omega‐3 Fatty Acids on Growth Factor‐mediated Proliferation and Migration in Human Prostate Cancer Cells

Abstract

Both in vitro and in vivo experiments have shown that omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have promising inhibitory effects on prostate cancer cell growth and invasion. Omega-3 fatty acids act via several potential molecular mechanisms that include their action as agonists at free fatty acid receptors (FFARs), which are G protein-coupled receptors. Two FFARs that bind omega-3 fatty acids, FFA1 and FFA4, are expressed in DU145 and PC-3 cells, two late-stage human prostate cancer cell lines. Our group has shown that both EPA and TUG-891, a synthetic, highly selective FFA4 (formerly GPR120) agonist, completely inhibit lysophosphatidic acid (LPA)- and epidermal growth factor (EGF)-mediated proliferation and migration in DU145 and PC-3 cells. The FFA4 agonists also significantly inhibit proliferation induced by fetal bovine serum. The inhibitory effects are readily reversed upon removal of TUG-891 or EPA., demonstrating that the FFA4 agonists must be continually present in order to inhibit proliferation To further confirm the involvement of FFA4, we utilized siRNA to decrease FFA4 expression in DU145 and PC-3 cells. We found that FFA4 knockdown eliminates the inhibitory effects of EPA and TUG-891 on proliferation and migration in both cell lines, in response to both LPA and EGF. Our data suggest that FFA4 is a promising therapeutic target in prostate cancer.