Different roles of GPR120 and GPR40 in the acquisition of malignant properties in pancreatic cancer cells

Fukushima, Kaori; Yamasaki, Eri; Ishii, Shigeyuki; Tomimatsu, Ayaka; Takahashi, Kazuhisa; Hirane, Miku; Fukushima, Nobuyuki; Honoki, Kanya; Tsujiuchi, Toshifumi

doi:10.1016/j.bbrc.2015.08.050

Cited by 35 publications

(25 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A 251 bp product corresponding to hGPR120 was also detected by PCR in HUVECs, HAoSMCs and HCaECs ( Figure 1D). The same product was obtained in HEK293 cells overexpressing GPR120 (HEK293+GPR120(s)) and PanC-1 cells, a cell known to express GPR120 and GPR40 (44 Figure 2B). While non-transfected HEK293 may express low levels of GPR40 protein but not mRNA ( Figure 1C and 1A), this is apparently not of functional consequence.…”

Section: Resultssupporting

confidence: 53%

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

Park

Herrnreiter

Pfister

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Endothelium-derived epoxyeicosatrienoic acids (EETs) have numerous vascular activities mediated by G protein-coupled receptors. Long-chain free fatty acids and EETs activate GPR40, prompting us to investigate the role of GPR40 in some vascular EET activities. 14,15-EET, 11,12-EET, arachidonic acid, and the GPR40 agonist GW9508 increase intracellular calcium concentrations in human GPR40-overexpressing HEK293 cells (EC 50 = 0.58 ± 0.08 µM, 0.91 ± 0.08 µM, 3.9 ± 0.06 µM and 19 ± 0.37 nM, respectively). EETs with cisand trans-epoxides had similar activities, whereas substitution of a thiirane sulfur for the epoxide oxygen decreased the activities. 8,9-EET, 5,6-EET, and the epoxide hydrolysis products 11,12-and 14,15-vicdihydroxyeicosatrienoic acids were less active than 11,12-EET. The GPR40 antagonist GW1100 and siRNA-mediated GPR40 silencing blocked the EET-and GW9508-induced calcium increases. EETs are weak GPR120 agonists. GPR40 expression was detected in human and bovine endothelial cells (ECs), smooth muscle cells, and arteries. 11,12-EET concentration-dependently relaxed preconstricted coronary arteries; however, these relaxations were not altered by GW1100. In human ECs, 11,12-EET increased MAP kinase-mediated ERK phosphorylation, phosphorylation and levels of connexin-43 (Cx43), and expression of cyclooxygenase-2 (COX-2), all of which were inhibited by GW1100 and the MAP kinase inhibitor U0126. Moreover, siRNA-mediated GPR40 silencing decreased 11,12-EETinduced ERK phosphorylation. These results indicated that GPR40 is a low-affinity EET receptor in vascular cells and arteries. We conclude that epoxidation of arachidonic acid to EETs enhances GPR40 agonist activity and that 11,12-EET stimulation of GPR40 increases Cx43 and COX-2 expression in ECs via ERK phosphorylation. INTRODUCTIONhttp://www.jbc.org/cgi

show abstract

Section: Resultssupporting

confidence: 53%

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

Park

Herrnreiter

Pfister

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Overexpression of GPR120 in colorectal carcinomas has been associated with angiogenic switching and cell motility (33). Similarly, in pancreatic cancer cell lines, down-regulation of GPR120 prevented cell migration (34). In contrast, in prostate cancer, GPR120 signaling seems to have an antitumor effect (35).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

“…While studies in prostate cancer cell lines have suggested FFA4 to have protective anticancer effects, 337 in pancreatic cancer cell lines FFA4 enhanced motility, invasion, and tumorigenicity. 338 Most interestingly, FFA4 expression appeared to be significantly induced in human colorectal carcinoma cells and tissues, and indeed, FFA4 appears to function as a tumor-promoting receptor in these cells. 339 Taken together, these findings suggest FFA4 may represent a target for novel anticancer therapeutics, but the mode of action (agonism vs antagonism) is not yet entirely clear and may vary between specific cancer types.…”

Section: Expression Of Ffa4mentioning

confidence: 96%

Complex Pharmacology of Free Fatty Acid Receptors

et al. 2016

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond simple competitive agonism or antagonism by ligands interacting with the orthosteric binding site of the receptor to incorporate concepts of allosteric agonism, allosteric modulation, signaling bias, constitutive activity, and inverse agonism. Herein, we consider how evolving concepts of GPCR pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or "free" fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets for the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential.

show abstract

Different roles of GPR120 and GPR40 in the acquisition of malignant properties in pancreatic cancer cells

Cited by 35 publications

References 21 publications

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

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

Complex Pharmacology of Free Fatty Acid Receptors

Contact Info

Product

Resources

About