Abstract
Many key actions of ω-3 (n-3) fatty acids have recently been shown to be mediated by two G protein-coupled receptors (GPCRs) in the free fatty acid receptor (FFAR) family, FFA1 (GPR40) and FFA4 (GPR120). n-3 Fatty acids inhibit proliferation of human breast cancer cells in culture and in animals. In the current study, the roles of FFA1 and FFA4 were investigated. In addition, the role of cross-talk between GPCRs activated by lysophosphatidic acid (LPA), and the tyrosine kinase receptor activated by epidermal growth factor (EGF), was examined. In MCF-7 and MDA-MB-231 human breast cancer cell lines, both LPA and EGF stimulated proliferation, Erk activation, Akt activation, and CCN1 induction. LPA antagonists blocked effects of LPA and EGF on proliferation in MCF-7 and MDA-MB-231, and on cell migration in MCF-7. The n-3 fatty acid eicosopentaneoic acid inhibited LPA- and EGF-induced proliferation in both cell lines. Two synthetic FFAR agonists, GW9508 and TUG-891, likewise inhibited LPA- and EGF-induced proliferation. The data suggest a major role for FFA1, which was expressed by both cell lines. The results indicate that n-3 fatty acids inhibit breast cancer cell proliferation via FFARs, and suggest a mechanism involving negative cross-talk between FFARS, LPA receptors, and EGF receptor.
Highlights
Our group recently demonstrated that the inhibitory effects of ω-3 fatty acids on prostate cancer cell proliferation are mediated by FFA4, a G protein-coupled receptor in the free fatty acid receptor (FFAR) family [1]
Cells were serum‐starved before treatments in order to to remove confounding effects of lysophosphatidic acid (LPA) contained in serum, and to provide a baseline for testing effects remove confounding effects of LPA contained in serum, and to provide a baseline for testing effects of of growth factors
FFA4 intothe breast cancer cell lines.cells. These results indicate that the roles of both FFA1 and FFA4 need betwo considered in breast cancer need in breast breast cancer cancer cells
Summary
Our group recently demonstrated that the inhibitory effects of ω-3 fatty acids on prostate cancer cell proliferation are mediated by FFA4, a G protein-coupled receptor in the free fatty acid receptor (FFAR) family [1]. The purpose of the current study was to determine whether FFARs mediate similar inhibitory effects in human breast cancer cells. Effects of n-3 FAs in prostate cancer have been debated [2], there is relatively strong evidence supporting a preventative effect of n-3 FA consumption on many human cancers [3], including breast cancer [4]. The direct effects of n-3 metabolites on cancer cells, as compared to their anti-inflammatory effects, are
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