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

Houthuijzen, J. M. et al. (2017) Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance. FASEB Journal, 31(5), pp. 2195-2209. (doi: 10.1096/fj.201601248R) (PMID:28183801) (PMCID:PMC5388545)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hudson, Dr Brian and Milligan, Professor Graeme
Authors: Houthuijzen, J. M., Oosterom, I., Hudson, B. D., Hirasawa, A., Daenen, L. G.M., McLean, C. M., Hansen, S. V.F., Jaarsveld, M. T.M., Peeper, D. S., Sadatmand, S. J., Roodhart, J. M.L., van de Lest, C. H.A., Ulven, T., Ishihara, K., Milligan, G., and Voest, E. E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:FASEB Journal
Publisher:Federation of American Society of Experimental Biology
ISSN:0892-6638
ISSN (Online):1530-6860
Published Online:09 February 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in FASEB Journal 31(5):2195-2209
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
618921GPR120: a G protein-coupled receptor with the potential to regulate insulin secretion and inflammationGraeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/K019864/1RI MOLECULAR CELL & SYSTEMS BIOLOGY