Journal article
Omega-3 fatty acids and other FFA4 agonists inhibit growth factor signaling in human prostate cancer cells
The Journal of pharmacology and experimental therapeutics, Vol.352(2), pp.380-394
02/2015
Handle:
https://hdl.handle.net/2376/111860
PMCID: PMC4293432
PMID: 25491146
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.
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Details
- Title
- Omega-3 fatty acids and other FFA4 agonists inhibit growth factor signaling in human prostate cancer cells
- Creators
- Ze Liu - Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WashingtonMandi M Hopkins - Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WashingtonZhihong Zhang - Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WashingtonChrystal B Quisenberry - Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WashingtonLouise C Fix - Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WashingtonBrianna M Galvan - Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WashingtonKathryn E Meier - Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington kmeier@wsu.edu
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.352(2), pp.380-394
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- United States
- Grant note
- T32 GM008336 / NIGMS NIH HHS UL1 RR025014 / NCRR NIH HHS
- Identifiers
- 99900547327401842
- Language
- English
- Resource Type
- Journal article