Fatty acid 16:4(n‐3) stimulates a GPR120‐induced signaling cascade in splenic macrophages to promote chemotherapy resistance.

Abstract

Although chemotherapy is designed to eradicate tumor cells, it also has significant effects on normal tissues. The platinum-induced fatty acid 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid) induces systemic resistance to a broad range of DNA-damaging chemotherapeutics. We show that 16:4(n-3) exerts its effect by activating splenic F4/80+/CD11blow macrophages, which results in production of chemoprotective lysophosphatidylcholines (LPCs). Pharmacologic studies, together with analysis of expression patterns, identified GPR120 on F4/80+/CD11blow macrophages as the relevant receptor for 16:4(n-3). Studies that used splenocytes from GPR120-deficient mice have confirmed this conclusion. Activation of the 16:4(n-3)-GPR120 axis led to enhanced cPLA2 activity in these splenic macrophages and secretion of the resistance-inducing lipid mediator, lysophosphatidylcholine(24:1). These studies identify a novel and unexpected function for GPR120 and suggest that antagonists of this receptor might be effective agents to limit development of chemotherapy resistance.—Houthuijzen, J. M., Oosterom, I., Hudson, B. D., Hirasawa, A., Daenen, L. G. M., McLean, C. M., Hansen, S. V. F., van Jaarsveld, M. T. M., Peeper, D. S., Jafari Sadatmand, S., Roodhart, J. M. L., van de Lest, C. H. A., Ulven, T., Ishihara, K., Milligan, G., Voest, E. E. Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance.

α‐Linolenic acid‐derived metabolites from gut lactic acid bacteria induce differentiation of anti‐inflammatory M2 macrophages through G protein‐coupled receptor 40

“…These findings may be in the line with previous study, which has indicated that PKC activation following GPCR40 activation by v-3 PUFAs including docosahexaenoic acid and ALA induced receptor internalization and ERK1/2 phosphorylation (38). While shown that GPCR40 and -120 in splenic macrophages have function in different manner (39), the molecular mechanistic details and the biologic significance regarding why recognition by GPCR40 rather than GPCR120 may promote M2 macrophage differentiation remain to be seen. Therefore, further experiments are required to verify the functional roles of GPCRs, including GPCR40 and -120, in macrophage differentiation.…”

FFA4/GPR120: Pharmacology and Therapeutic Opportunities

“…A challenge for the translation of these ideas to humans is whether, even with dietary supplementation, levels of such fatty acids are likely sufficient to engage the receptor to a substantial level [35] . This question is further complicated by the fact that quantitatively more prevalent fatty acids are also able to activate FFA4 [20] , while specific, but relatively uncommon, fatty acids or their derivatives, which do not display substantially greater potency at FFA4 in vitro , are capable of generating biological functions with apparent high potency and that are lacking in FFA4-knockout animals [36] or are reduced with knock down of this receptor in model cell systems [37] .…”

“…For example, Suzuki et al [50] modified PPARγ-active molecules to generate a ligand, 4-{4-[2-(phenyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-butyric acid, later named NCG21 ( Table 1 ), which displayed modest selectivity for FFA4 over FFA1, but also only modest potency [51] . With appropriate recognition that it probably acts as a combined FFA4 and FFA1 activator, this compound has been used recently alongside other more-selective ligands to help unravel the contribution of each long-chain fatty acid receptor to the ability of the omega-3 fatty acid, hexadeca-4,7,10,13-tetraenoic acid [16:4(n-3)], to generate systemic resistance to the DNA-damaging chemotherapeutic cisplatin [36] (discussed below). In the first significant advance in developing FFA4-selective agonist ligands, Shimpukade et al [52] reported the ortho -biphenyl ligand 4-{[4-fluoro-4′-methyl(1,1′-biphenyl)-2-yl]methoxy}-benzenepropanoic acid (TUG-891) ( Table 1 ).…”

“…Although there is no comprehensive analysis of these features for many ligands, which are rarely reported beyond humans versus mice, the major reason for the lower selectivity between the mouse orthologues is their higher potency at mouse FFA1 rather than reduced potency at mouse FFA4. In practise, although a potent and selective FFA4 agonist in human cells and tissues, TUG-891 is best described as a dual FFA4 and FFA1 agonist in equivalent tissues from rodents [36] . More recently reported compounds have provided greater levels of selectivity.…”

“…This compound, and a closely related molecule, 4-methyl- N -(9 H -thioxanthen-9-yl)benzenesulfonamide (TUG-1506) [60] ( Table 1 ), act as noncompetitive, negative allosteric modulators of the action of a range of FFA4 agonist chemotypes [60] . Although neither competitive nor displaying more than moderate affinity (approximately 10 nM) [60] for the receptor, AH-7614 has recently been used in a range of studies; for example, to confirm a specific role for FFA4 as the long-chain fatty acid receptor on splenic macrophages responsible for release of a lysophosphatidic acid species that is able to produce systemic resistance to platinum-containing chemotherapeutics [36] ; to identify a role of the receptor in activation of brown fat [61] ; to explore whether various effects of arachidonic acid are produced via FFA4 [62] ; and the contribution of FFA4 to docosahexaenoic acid [20:6(n-3)]-mediated effects in GnRH-producing neurones [63] . However, as noted by Watterson et al [60] , AH-7614 is a simple xanthene-containing chemical and, although this molecule does not block agonist effects at FFA1 [60] , other potential sites of action have not been explored.…”