Omega-3 Fatty Acids and Other FFA4 Agonists Inhibit Growth Factor Signaling in Human Prostate Cancer Cells

• Published in: The Journal of pharmacology and experimental therapeutics 2015-02, Vol.352 (2), p.380-394
• Main Authors: Liu, Ze, Hopkins, Mandi M., Zhang, Zhihong, Quisenberry, Chrystal B., Fix, Louise C., Galvan, Brianna M., Meier, Kathryn E.
• Format: Article
• Language: English
• Subjects: Anticarcinogenic Agents - pharmacology; Cell Culture Techniques; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cellular and Molecular; Fatty Acids, Omega-3 - pharmacology; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Male; Prostatic Neoplasms - pathology; Receptors, G-Protein-Coupled - agonists; Signal Transduction - drug effects
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.114.218974

Omega-3 fatty acids (n-3 FAs) are proposed to have many beneficial effects on human health. However, the mechanisms underlying their potential cancer preventative effects are unclear. G protein–coupled receptors (GPCRs) of the free fatty acid receptor (FFAR) family, FFA1/GPR40 and FFA4/GPR120, specifically bind n-3 FAs as agonist ligands. In this study, we examined the effects of n-3 FAs in human prostate cancer cell lines. Initial studies established that the long-chain n-3 FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid, inhibit proliferation of DU145 cells in response to lysophosphatidic acid (LPA), a mitogenic lipid mediator. When added alone to serum-starved DU145 cells, EPA transiently activates signaling events, including p70S6K phosphorylation. However, when added 15 minutes prior to LPA, EPA suppresses LPA-induced activating phosphorylations of ERK, FAK, and p70S6K, and expression of the matricellular protein CCN1. The rapid onset of the inhibitory action of EPA suggested involvement of a GPCR. Further studies showed that DU145 and PC-3 cells express mRNA and protein for both FFA4 and FFA1. TUG-891 (4-[(4-fluoro-4′-methyl[1,1′-biphenyl]-2-yl)methoxy]-benzenepropanoic acid), a selective agonist for FFA4, exerts inhibitory effects on LPA- and epidermal growth factor–induced proliferation and migration, similar to EPA, in DU145 and PC-3 cells. The effects of TUG-891 and EPA are readily reversible. The FFA1/FFA4 agonist GW9508 (4-[[(3-phenoxyphenyl)methyl]amino]-benzenepropranoic acid) likewise inhibits proliferation at doses that block FFA4. Knockdown of FFA4 expression prevents EPA- and TUG-891–induced inhibition of growth and migration. Together, these results indicate that activation of FFA4 initiates signaling events that can inhibit growth factor–induced signaling, providing a novel mechanism for suppression of cancer cell proliferation.