Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance.
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+/CD11blowmacrophages, which results in production of chemoprotective lysophosphatidylcholines (LPCs). Pharmacologic studies, together with analysis of expression patterns, identified GPR120 on F4/80+/CD11blowmacrophages 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 cPLA2activity 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.
Department of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Julia M
JM
Houthuijzen
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Ilse
I
Oosterom
Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, University of Glasgow, Glasgow, United Kingdom.
Brian D
BD
Hudson
Department of Genomic Drug Discovery Science, Kyoto University, Kyoto, Japan.
Akira
A
Hirasawa
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Laura G M
LGM
Daenen
Department of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Chelsea M
CM
McLean
Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark.
Steffen V F
SVF
Hansen
Department of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Marijn T M
MTM
van Jaarsveld
Department of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Daniel S
DS
Peeper
Department of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Sahar
S
Jafari Sadatmand
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Jeanine M L
JML
Roodhart
Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Chris H A
CHA
van de Lest
Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark.
Trond
T
Ulven
National Research Institute of Fisheries Science, Kanazawaku, Japan.
Kenji
K
Ishihara
Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, University of Glasgow, Glasgow, United Kingdom.
Graeme
G
Milligan
Department of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Emile E
EE
Voest
D000818:Animals; D004351:Drug Resistance / Q000502:physiology; D015525:Fatty Acids, Omega-3 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
C498007:FFAR4 protein, mouse; D015525:Fatty Acids, Omega-3; D043562:Receptors, G-Protein-Coupled
FFAR1; FFAR4; GPR40; PIFA