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  • To investigate an involvement of GPR and GPR in the


    To investigate an involvement of GPR120 and GPR40 in the enhancement of cell motile activity of MG-63 cells, highly migratory (MG63-R7) PRT-060318 were established from MG-63 cells (Fig. 2A). The expression level of GPR120 gene was significantly higher in MG63-R7 cells than in MG-63 cells, while no change of GPR40 expressions was observed (Fig. 2B). The cell growth rate of MG63-R7 cells was significantly lower than that of MG-63 cells (Fig. 2C). GW9508 had no impact on the cell growth activities of both cells (Fig. 2D). The cell motile activity of MG63-R7 cells was approximately 200 times higher than that of MG-63 cells. GW9508 increased the cell motile activities of both cells (Fig. 3A and B). In cell invasion assay, MG63-R7 cells showed the high invasive activity, compared with MG-63 cells. The invasive activity of MG63-R7 cells was increased by GW9508, but not MG-63 cells (Fig. 3C). On the other hand, the activation of MMP-2 was significantly lower in MG63-R7 cells than in MG-63 cells. GW9508 had no impact on MMP-2 activations. No activation of MMP-9 was not detected in both cells (Fig. 3D and E). It is considered that MMP-2 and MMP-9 activations facilitate tumor progression, including invasion and metastasis [23], [24]. Since MG63-R7 cells indicated the low MMP-2 activation, it seems that the high cell invasive rate observed in the cell invasion assay may be due to the intrinsic cell motile activity of MG63-R7 cells. Before cell motility assay, cells were pretreated with GW1100 (1 μM), which is an antagonist of GPR40 [20], [21]. GW1100 increased the cell motile activity of MG63-R7 cells in the presence of GW9508, similar as observed with MG-63 cells (Fig. 4A). Moreover, to confirm the effects of GPR120 on the cell motile activity of MG63-R7 cells, GPR120 knockdown (MG-R7-120) cells were generated from MG63-R7 cells. The cell motile activity of MG-R7-120 cells was significantly lower than that of MG-R7-R (control) cells. While GW9508 elevated the cell motile activity of MG-R7-R cells, the cell motile activity of MG-R7-120 cells was suppressed by GW9508 (Fig. 4B). In addition, MG-R7-120 cells indicated the low invasive activity, compared with MG-R7-R cells (Fig. 4C). In gelatin zymography, the activation of MMP-2 was significantly higher in MG-R7-120 cells than in MG-R7-R cells, while no activation of MMP-9 was detected. GW9508 did not affect MMP-2 activations in both cells (Fig. 4D and E). Taken together, these results showed that GPR120 positively and GPR40 negatively regulated the cell motile activity of highly migratory cells. In contrast, the activity of MMP-2 in highly cell migratory cells was suppressed by GPR120. Our recent studies showed that GPR120 enhanced and GPR40 suppressed the activation of MMP-2 in pancreatic cancer cells, whereas the activation of MMP-2 in lung cancer cells was stimulated by GPR40 [15], [17]. Therefore, the effects of GPR120 and GPR40 on cellular functions may be dependent on the types of cancer cells.
    Conflict of interest statement
    Acknowledgements This work was supported by JSPS KAKENHI Grant Number 24590493 and by Grants from the Faculty of Science and Engineering, Kindai University.
    Fibrosis is characterized by the excessive accumulation of extracellular matrix in damaged or inflamed tissues, and it is the common pathological outcome of many inflammatory and metabolic diseases. Numerous clinical conditions can lead to organ fibrosis and functional failure; in many disorders, acute or persistent inflammation is crucial to trigger the fibrotic response. The production of various profibrotic cytokines and growth factors by innate inflammatory cells results in the recruitment and activation of extracellular matrix–producing myofibroblasts. There is currently a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. Free fatty acids (FFAs) are essential nutrients that exert various biological effects and have been implicated in many diseases, playing protective or harmful roles depending on the context. Besides their effects on intracellular metabolism and nuclear receptors, studies in the past 15 years have shown that FFAs can activate several cell surface G protein–coupled receptors, including FFA receptor 1 (GPR40) and GPR84. GPR40 and GPR84 show distinct characteristics in both fatty acid binding and biological effects. GPR40 is activated by both medium-chain FFAs (eg, decanoic acid) and long-chain FFAs (eg, linoleic acid), and is coupled to G or G proteins. GPR84 is responsive to medium-chain FFAs only and activates almost exclusively pertussis toxin–sensitive G signaling pathways. In addition, GPR40 and GPR84 exhibit distinct tissue distribution profiles. GPR40 is abundantly expressed in pancreatic β cells, where it enhances glucose-mediated insulin secretion. Accordingly, several GPR40 agonists have advanced to clinical trials for type 2 diabetes. However, the actions of GPR40 may not be limited to insulin secretion. GPR40 is also expressed in enteroendocrine cells of the gastrointestinal tract and PRT-060318 may mediate release of glucagon-like peptide-1 and cholecystokinin secretion., In addition, GPR40 is expressed in murine skin and may serve to limit and attenuate inflammation. Recent studies have also involved GPR40 in regulation of pain perception and sensing taste of fatty acids. Finally, GPR40 has been shown to be expressed in the rat kidney and in a subset of murine kidney tubules, including the cortical collecting duct. Moreover, in human renal proximal tubule epithelial HK-2 cells, activation of GPR40 with the synthetic agonist GW9508 reduced cisplatin-induced apoptosis.