SOCS3 Transactivation by PPARγ Prevents IL-17-Driven Cancer Growth

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 12; pp. 3578 - 3590
• Main Authors: BERGER, Hélène, VEGRAN, Frédérique, CHEVRIAUX, Angélique, REBE, Cédric, RYFFEL, Bernhard, POT, Caroline, HICHAMI, Aziz, DESVERGNE, Béatrice, GHIRINGHELLI, François, APETOH, Lionel, CHIKH, Madijd, GILARDI, Federica, LADOIRE, Sylvain, BUGAUT, Hélène, MIGNOT, Grégoire, CHALMIN, Fanny, BRUCHARD, Mélanie, DERANGERE, Valentin
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-06-2013
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Blotting, Western; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; Cell Differentiation - drug effects; Cell Line, Tumor; Diet; Docosahexaenoic Acids - administration & dosage; Docosahexaenoic Acids - pharmacology; Female; Interleukin-17 - metabolism; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - pathology; Mammary Neoplasms, Experimental - prevention & control; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pharmacology. Drug treatments; PPAR gamma - agonists; PPAR gamma - genetics; PPAR gamma - metabolism; Promoter Regions, Genetic - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Th17 Cells - drug effects; Th17 Cells - metabolism; Transcriptional Activation; Tumor Burden - drug effects; Tumor Burden - genetics; Tumors; Prevention; Growth; Suppressor of cytokine signaling 3; Suppressor of cytokine signalling; Malignant tumor; Gene expression; PPAR-γ receptor; Interleukin 17; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-4018

Activation of the transcription factor PPARγ by the n-3 fatty acid docosahexaenoic acid (DHA) is implicated in controlling proinflammatory cytokine secretion, but the intracellular signaling pathways engaged by PPARγ are incompletely characterized. Here, we identify the adapter-encoding gene SOCS3 as a critical transcriptional target of PPARγ. SOCS3 promoter binding and gene transactivation by PPARγ was associated with a repression in differentiation of proinflammatory T-helper (TH)17 cells. Accordingly, TH17 cells induced in vitro displayed increased SOCS3 expression and diminished capacity to produce interleukin (IL)-17 following activation of PPARγ by DHA. Furthermore, naïve CD4 T cells derived from mice fed a DHA-enriched diet displayed less capability to differentiate into TH17 cells. In two different mouse models of cancer, DHA prevented tumor outgrowth and angiogenesis in an IL-17-dependent manner. Altogether, our results uncover a novel molecular pathway by which PPARγ-induced SOCS3 expression prevents IL-17-mediated cancer growth.