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)

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 > School of Molecular Biosciences
• 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
61892	1	GPR120: a G protein-coupled receptor with the potential to regulate insulin secretion and inflammation	Graeme Milligan	Biotechnology and Biological Sciences Research Council (BBSRC)	BB/K019864/1	RI MOLECULAR CELL & SYSTEMS BIOLOGY