RESUMEN
The nuclear receptor peroxisome proliferator-activated receptor ß/δ (PPARß/δ) is a lipid ligand-inducible transcription factor associated with macrophage polarization. However, its function in tumor-associated macrophages (TAMs) has not been investigated to date. Here, we report the PPARß/δ-regulated transcriptome and cistrome for TAMs from ovarian carcinoma patients. Comparison with monocyte-derived macrophages shows that the vast majority of direct PPARß/δ target genes are upregulated in TAMs and largely refractory to synthetic agonists, but repressible by inverse agonists. Besides genes with metabolic functions, these include cell type-selective genes associated with immune regulation and tumor progression, e.g., LRP5, CD300A, MAP3K8 and ANGPTL4. This deregulation is not due to increased expression of PPARß/δ or its enhanced recruitment to target genes. Instead, lipidomic analysis of malignancy-associated ascites revealed high concentrations of polyunsaturated fatty acids, in particular linoleic acid, acting as potent PPARß/δ agonists in macrophages. These fatty acid ligands accumulate in lipid droplets in TAMs, thereby providing a reservoir of PPARß/δ ligands. These observations suggest that the deregulation of PPARß/δ target genes by ligands of the tumor microenvironment contributes to the pro-tumorigenic polarization of ovarian carcinoma TAMs. This conclusion is supported by the association of high ANGPTL4 expression with a shorter relapse-free survival in serous ovarian carcinoma.
Asunto(s)
Ácido Linoleico/genética , Macrófagos/patología , Neoplasias Ováricas/sangre , Neoplasias Ováricas/genética , PPAR delta/genética , PPAR-beta/genética , Microambiente Tumoral/genética , Animales , Estudios de Casos y Controles , Ácidos Grasos , Femenino , Humanos , Ligandos , Ácido Linoleico/sangre , Macrófagos/metabolismo , Ratones , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/genética , PPAR delta/sangre , PPAR-beta/sangreRESUMEN
The peroxisome proliferator-activated receptor subtypes PPARα, PPARß/δ, PPARγ are members of the steroid hormone receptor superfamily with well-established functions in transcriptional regulation. Here, we describe an unexpected cytoplasmic function of PPARß/δ. Silencing of PPARß/δ expression interferes with the expression of a large subset of interleukin-1ß (IL-1ß)-induced target genes in HeLa cells, which is preceded by an inhibition of the IL-1ß-induced phosphorylation of TAK1 and its downstream effectors, including the NFκBα inhibitor IκBα (NFKBIA) and the NFκBα subunit p65 (RELA). PPARß/δ enhances the interaction between TAK1 and the small heat-shock protein HSP27, a known positive modulator of TAK1-mediated IL-1ß signaling. Consistent with these findings, PPARß/δ physically interacts with both the endogenous cytoplasmic TAK1/TAB1 complex and HSP27, and PPARß/δ overexpression increases the TAK1-induced transcriptional activity of NFκB. These observations suggest that PPARß/δ plays a role in the assembly of a cytoplasmic multi-protein complex containing TAK1, TAB1, HSP27 and PPARß/δ, and thereby participates in the NFκB response to IL-1ß.