PPAR: The Portrait of a Target Ally to Cancer Chemopreventive Agents
Figure 1
Peroxisome
proliferator-activated receptor-γ and ligands: pathways
and functions. PPARγ protein exhibits a structural organization
consisting of three functional domains: an N-terminal domain, a DNA-binding
domain (DBD) and a carboxy-terminal ligand binding domain (LBD). PPARγ forms heterodimers with a second member of the
nuclear receptor family, the retinoic X receptor (RXR). Unliganded PPARγ suppresses transcription (pathway A) either by
interfering with key transcription factors (pathway A1) or through recruitment
of corepressors (CoRep) on a PPRE element (pathway A2). Ligand binding to PPARγ (pathway B) triggers conformational changes that lead
to dissociation of corepressors (CoRep) and subsequent association of
coactivators (CoAct). The complex is binding to PPREs and triggers
transcription (pathway B). PPARs ligands can also
exert their action through PPARγ-independent mechanisms
also (pathway C). For instance in NSCLC cell lines activation of TNF-TRAIL
induce apoptosis, while PGE2 degradation, trough 15-hydroxyprostagladin dehydrogenase induction, results in enhanced epithelial
differentiation. In endothelial cells PPARγ
ligands can markedly boost expression of CD36 which
functions as the receptor of endogenous antiangiogenic molecule
thrombospondin-1, thereby potentiating the apoptotic response. (PFAs: polyunsaturated
fatty acids, TZDs: thiazolidinediones, PPRE: peroxisome proliferator response
element, TNF: tumor necrosis factor, TRAIL: TNF-related apoptosis-inducing
ligand, NSCLC: non-small cell lung carcinoma).