title: Omega-3 fatty acids and other FFA4 agonists inhibit growth factor signaling in human prostate cancer cells.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington.
authors.forename: Ze
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington.
authors.forename: Mandi M
authors.initials: MM
authors.lastname: Hopkins
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington.
authors.forename: Chrystal B
authors.initials: CB
authors.lastname: Quisenberry
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Fix
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington.
authors.forename: Brianna M
authors.initials: BM
authors.lastname: Galvan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington kmeier@wsu.edu.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Meier
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016588:Anticarcinogenic Agents; C519853:FFAR4 protein, human; D015525:Fatty Acids, Omega-3; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled