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.
Footnotes
- Received August 3, 2014.
- Accepted November 25, 2014.
Z.L. and M.M.H. contributed equally to this work.
This work was supported by the College of Pharmacy at Washington State University (WSU), and by a Collaborative Translational Seed Grant [UL1-RR025014] to Z.Z. from the Institute of Translational Health Sciences at the University of Washington. C.R.Q. was the recipient of a Nutrition and Exercise Physiology Undergraduate Research Fellowship from the WSU College of Pharmacy. M.M.H., a member of the Graduate Program in Pharmaceutical Sciences in the College of Pharmacy, also received support from the National Institutes of Health National Institute of General Medical Sciences Protein Biotechnology Training Program at WSU [Grant T32-GM008336]. B.M.G. was the recipient of a Summer Undergraduate Research Fellowship funded by the American Society for Pharmacology and Experimental Therapeutics, and by the College of Pharmacy.
Liu Z (2013) Effects of Omega-3 Fatty Acids on Prostate Cancer Cells. M.Sc. thesis, Washington State University, Spokane, WA.
Aspects of this study have been previously discussed in the following abstracts: Zhang Z and Meier KE (2011) Effects of LPA antagonist and PLD inhibitor on proliferation of human prostate cancer cell lines. Experimental Biology 2011; 2011 Apr 9–13; Washington, DC; Zhang Z, Bailey CR, and Meier KE (2012) Effects of lysophosphatidic acid on CCN1 expression in human prostate cancer cell lines. Experimental Biology 2012; 2012 Apr 22–25; San Diego, CA; Hopkins MM, Liu Z, and Meier KE (2013) Effects of GPR120 agonists on lysophosphatidic acid signaling in prostate cancer cells. Southeast Regional Lipid Conference; 2013 Sept 13–15; Cashiers, NC; Hopkins MM, Liu Z, and Meier KE (2014) Effects of eicosapentaenoic acid and the GPR120 agonist TUG-891 on lysophosphatidic acid signaling in prostate cancer cells. Experimental Biology 2014; 2014 Apr 27–30; San Diego, CA; and Hopkins MM, Liu Z, Galvan BM, and Meier KE (1014) Omega-3 fatty acids inhibit LPA- and EGF-induced proliferation of human prostate cancer cells by acting as agonists for free fatty acid receptor 4 (FFA4). Southeast Regional Lipid Conference; 2014 Nov 5–7; Cashiers, NC.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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