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  • While there have been a variety of recent

    2022-05-21

    While there have been a variety of recent reviews on the signaling and physiological effects of FFA4, particularly towards its anti-inflammatory effects, the goal of this research update is to present the most recent details on the role of FFA4 in human cancers. The known contributions of FFA4 towards promotion or inhibition of cancer cell proliferation, migration, invasion and tumorigenesis are described based on cancer tissue type below and also summarized in Table 1.
    Prostate cancer cell lines The dietary role of fats, particularly PUFAs, in the in vivo pathogenesis of human prostate carcinomas has proven to be controversial with conflicting results, yet the evidence is decidedly more stout in cell culture based models of prostate cancer. These models typically utilize PC-3 and DU145 cells that are androgen-insensitive and metastatic, as well as LNCaP cells, which are androgen-sensitive but have less migratory capacity. Long-chain omega-3 PUFA such as DHA and EPA have previously been known to reduce androgen-dependent proliferation of these cell types [37], [38]. In other cases, omega-6 PUFA stimulate proliferation and migration of prostate cancer cell lines, while this effect is specifically inhibited by omega-3 PUFA [39]. Mice fed omega-3 PUFA-enriched diets exhibited decreased expression of proliferation-inducing genes, increased prostate apoptosis, and decreased prostatic proliferation [40]. Conventionally, the mechanisms of PUFA-mediated prostate cancer inhibition were thought to occur due to intracellular metabolism of PUFA, leading to inhibition of enzymes such as cyclooxygenase and lipoxygenases, which influence cell growth and metastasis. Liu and colleagues were the first to show that both PC-3 and DU145 cell lines express FFA4, and that treatment with DHA or EPA inhibits lysophosphatidic CCT251545 analogue mg (LPA)-induced proliferation in both cell lines [41]. Omega-3 PUFA inhibited LPA-mediated signaling to proliferative pathways, where specifically, EPA reduced phosphorylation and subsequent activation of ERK1/2, FAK, and p70S6K, the latter of which acts via AKT signaling, and all of which are intricately involved in LPA-induced prostate cell proliferation [41]. Moreover, EPA inhibited transcription and translation of CCN1, an integrin-binding matricellular protein that is critical for prostate cell adhesion, migration, proliferation, and survivability. Interestingly, the effects of omega-3 PUFA were seen to occur on the order of minutes, suggesting a cell-surface receptor mediated mechanism. Indeed, in DU145 cells, the selective synthetic FFA4 agonist TUG-891 inhibited LPA-induced proliferation with an IC50 of 73 nM, compared to a relative potency of 5.7 μM for EPA [41], and these effects were mimicked in PC-3 cells and were also replicated upon use of EGF as the mitogenic stimulus [41]. The FFA1/FFA4 agonist GW9508, which displays moderate selectively for FFA1, displayed an IC50 of 950 nM, an effect much higher than its published EC50 of 50 nM for FFA1, and more consistent with its approximately 2 μM potency for FFA4 [42]. Ultimately, TUG-891 displayed the highest potential for inhibition of LPA- or serum- induced proliferation of DU145 and PC-3 cells, and this work demonstrated that serum-induced proliferation resumes upon removal of TUG-891, further supporting FFA4 involvement, as the agonist must be continuously present to inhibit proliferation in the face of constant mitogenic sources [41]. The same reversal was observed with EPA, which as a fatty acid, has the potential to be readily incorporated in phospholipids within prostate cancer cells to exert non-receptor mediated effects via changes in membrane fluidity and dynamics, as well as generation of intracellularly bioactive omega-3 metabolites [43]. Since previous results had shown that omega-3 PUFA can modulate PC-3 cell migration [39], these authors also assessed the role of FFA4 in LPA- and EGF-mediated migration of both DU145 and PC-3 cells. In both cells lines, EPA and TUG-891 treatment significantly reduced cell migration that was induced by either LPA or EGF, to the degree that the mitogen effect was nearly fully inhibited [41]. Finally, siRNA mediated knockdown (KD) of FFA4 in DU145 or PC-3 cells had no effect on LPA- or serum-induced migration in the absence of FFA4 agonists. However, FFA4 knockdown eliminated TUG-891 and EPA mediated decreases of both cell proliferation and migration that were observed in scrambled siRNA transfected DU145 and PC-3 cells at 48 and 72 h. This suggests that FFA4 is chiefly responsible for anti-cancer effects of omega-3 PUFA in these cells [41]. Interestingly, the study design involved treatment with siRNA and simultaneous drug (20 μM EPA or 1 μM TUG-891) and mitogen treatment (10 μM LPA or 10 nM EGF), a factor that allows for FFA4 agonists to initiate anti-proliferative and anti-migration effects prior to knockdown of the receptor (i.e., the receptor is still expressed at the beginning of the experiment). Yet, this element was not sufficient to inhibit proliferation over the longer time course of days, and taken together with the reversibility results mentioned previously, suggests that the inhibitory activity of FFA4 agonists requires stable and continued agonism of the receptor to oppose the continuous presence of mitogen.