Macrophage PPARγ inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone.
Tumor-associated macrophage (TAM) significantly contributes to cancer progression. Human cancer is enhanced by PPARγ loss-of-function mutations, but inhibited by PPARγ agonists such as TZD diabetes drugs including rosiglitazone. However, it remains enigmatic whether and how macrophage contributes to PPARγ tumor-suppressive functions. Here we report that macrophage PPARγ deletion in mice not only exacerbates mammary tumor development but also impairs the anti-tumor effects of rosiglitazone. Mechanistically, we identify Gpr132 as a novel direct PPARγ target in macrophage whose expression is enhanced by PPARγ loss but repressed by PPARγ activation. Functionally, macrophage Gpr132 is pro-inflammatory and pro-tumor. Genetic Gpr132 deletion not only retards inflammation and cancer growth but also abrogates the anti-tumor effects of PPARγ and rosiglitazone. Pharmacological Gpr132 inhibition significantly impedes mammary tumor malignancy. These findings uncover macrophage PPARγ and Gpr132 as critical TAM modulators, new cancer therapeutic targets, and essential mediators of TZD anti-cancer effects.
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, United States.
Wing Yin
WY
Cheng
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, United States.
HoangDinh
H
Huynh
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, United States.
Peiwen
P
Chen
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, United States.
Samuel
S
Peña-Llopis
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, United States.|Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, United States.
Yihong
0000-0003-0556-7017
Y
Wan
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D055786:Gene Knockout Techniques; D008264:Macrophages / Q000187:drug effects*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C115270:G2A receptor; D047495:PPAR gamma; D043562:Receptors, G-Protein-Coupled; D045162:Thiazolidinediones; D000077154:Rosiglitazone
Gpr132; PPARgamma; breast cancer; cancer biology; chromosomes; genes; macrophages; mouse; rosiglitazone
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