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

Julia M Houthuijzen; Ilse Oosterom; Brian D Hudson; Akira Hirasawa; Laura G M Daenen; Chelsea M McLean; Steffen V F Hansen; Marijn T M van Jaarsveld; Daniel S Peeper; Sahar Jafari Sadatmand; Jeanine M L Roodhart; Chris H A van de Lest; Trond Ulven; Kenji Ishihara; Graeme Milligan; Emile Voest

doi:10.1096/fj.201601248r

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

Julia M Houthuijzen, Ilse Oosterom, Brian D Hudson, Akira Hirasawa, Laura G M Daenen, Chelsea M McLean, Steffen V F Hansen, Marijn T M van Jaarsveld, Daniel S Peeper, Sahar Jafari Sadatmand, Jeanine M L Roodhart, Chris H A van de Lest, Trond Ulven, Kenji Ishihara, Graeme Milligan, Emile Voest

15 Citations (Scopus)

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⁺/CD11b^low macrophages, which results in production of chemoprotective lysophosphatidylcholines (LPCs). Pharmacologic studies, together with analysis of expression patterns, identified GPR120 on F4/80⁺/CD11b^low macrophages as the relevant receptor for 16:4(n-3). Studies that used splenocytes from GPR120-deficientmice 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 lipidmediator, lysophosphatidylcholine(24:1). These studies identify anovel and unexpected function for GPR120 and suggest that antagonists of this receptormightbe effective agents to limit development of chemotherapy resistance.

Original language	English
Journal	F A S E B Journal
Volume	31
Issue number	5
Pages (from-to)	2195-2209
Number of pages	15
ISSN	0892-6638
DOIs	https://doi.org/10.1096/fj.201601248r
Publication status	Published - May 2017
Externally published	Yes

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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. (2017). Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance. F A S E B Journal, 31(5), 2195-2209. https://doi.org/10.1096/fj.201601248r

Houthuijzen, JM, Oosterom, I, Hudson, BD, Hirasawa, A, Daenen, LGM, McLean, CM, Hansen, SVF, van Jaarsveld, MTM, Peeper, DS, Jafari Sadatmand, S, Roodhart, JML, van de Lest, CHA, Ulven, T, Ishihara, K, Milligan, G & Voest, E 2017, 'Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance', F A S E B Journal, vol. 31, no. 5, pp. 2195-2209. https://doi.org/10.1096/fj.201601248r

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

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-deficientmice 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 lipidmediator, lysophosphatidylcholine(24:1). These studies identify anovel and unexpected function for GPR120 and suggest that antagonists of this receptormightbe effective agents to limit development of chemotherapy resistance.",

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AU - Houthuijzen, Julia M

AU - Oosterom, Ilse

AU - Hudson, Brian D

AU - Hirasawa, Akira

AU - Daenen, Laura G M

AU - McLean, Chelsea M

AU - Hansen, Steffen V F

AU - van Jaarsveld, Marijn T M

AU - Peeper, Daniel S

AU - Jafari Sadatmand, Sahar

AU - Roodhart, Jeanine M L

AU - van de Lest, Chris H A

AU - Ulven, Trond

AU - Ishihara, Kenji

AU - Milligan, Graeme

AU - Voest, Emile

PY - 2017/5

Y1 - 2017/5

N2 - 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-deficientmice 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 lipidmediator, lysophosphatidylcholine(24:1). These studies identify anovel and unexpected function for GPR120 and suggest that antagonists of this receptormightbe effective agents to limit development of chemotherapy resistance.

AB - 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-deficientmice 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 lipidmediator, lysophosphatidylcholine(24:1). These studies identify anovel and unexpected function for GPR120 and suggest that antagonists of this receptormightbe effective agents to limit development of chemotherapy resistance.

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DO - 10.1096/fj.201601248r

M3 - Journal article

C2 - 28183801

SN - 0892-6638

VL - 31

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JF - F A S E B Journal

IS - 5

ER -

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

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