TY - JOUR
T1 - Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance
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 - Sadatmand, Sahar Jafari
AU - Roodhart, Jeanine M.L.
AU - Van De Lest, Chris H.A.
AU - Ulven, Trond
AU - Ishihara, Kenji
AU - Milligan, Graeme
AU - Voest, Emile E.
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.
KW - FFAR1
KW - FFAR4
KW - GPR40
KW - PIFA
UR - http://www.scopus.com/inward/record.url?scp=85019459788&partnerID=8YFLogxK
U2 - 10.1096/fj.201601248R
DO - 10.1096/fj.201601248R
M3 - Article
C2 - 28183801
AN - SCOPUS:85019459788
SN - 0892-6638
VL - 31
SP - 2195
EP - 2209
JO - FASEB Journal
JF - FASEB Journal
IS - 5
ER -