PPARgamma: The Portrait of a Target Ally to Cancer Chemopreventive Agents

Abstract

Peroxisome proliferator-activated receptor-gamma (PPARgamma), one of three ligand-activated transcription factors named PPAR, has been identified as a molecular target for cancer chemopreventive agents. PPARgamma was initially understood as a regulator of adipocyte differentiation and glucose homeostasis while later on, it became evident that it is also involved in cell differentiation, apoptosis, and angiogenesis, biological processes which are deregulated in cancer. It is now established that PPARgamma ligands can induce cell differentiation and yield early antineoplastic effects in several tumor types. Moreover, several bioactive natural products with cancer protecting potential are shown to operate through activation of PPARgamma. Overall, PPARgamma appears to be a prevalent target ally to cancer chemopreventive agents and therefore pursuing research in this area is of great relevance.

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).