Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is highly expressed in liposarcoma and promotes migration...

Aberrations of specialized metabolic pathways might be implicated in the development of neoplasias. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors with important functions in metabolism. PPARβ/δ and PPARγ act in the proliferation and differentiation of adipose tissue progenitor cells. Thus, a potential use of PPARγ agonists for the treatment of liposarcoma had been suggested, but clinical trials failed to detect beneficial effects. We show here that PPARδ is highly expressed in liposarcoma compared to lipoma and correlates with proliferation. Stimulation of liposarcoma cell lines with a specific PPARδ agonist increases proliferation, which is abolished by a PPARδ-siRNA or a specific PPARδ antagonist. Expression of the adipose tissue secretory factor leptin is lower in liposarcoma compared to lipoma and leptin reduces proliferation of liposarcoma cell lines. PPARδ activation stimulates cell migration whereas leptin diminishes it. We demonstrate that PPARδ directly represses leptin as: (a) leptin becomes down-regulated upon PPARδ activation; (b) PPARδ represses leptin promoter activity in different sarcoma cell lines; (c) deletion of a PPAR/RxR binding element in the leptin promoter abolishes repression by PPARδ; and (d) in chromatin immunoprecipitation we confirm in vivo binding of PPARδ to the leptin promoter. Our data suggest inhibition of PPARδ as a potential novel strategy to reduce liposarcoma cell proliferation.