The Role of PPARs in Cancer

Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. PPARalpha is mainly expressed in the liver, where it activates fatty acid catabolism. PPARalpha activators have been used to treat dyslipidemia, causing a reduction in plasma triglyceride and elevation of high-density lipoprotein cholesterol. PPARdelta is expressed ubiquitously and is implicated in fatty acid oxidation and keratinocyte differentiation. PPARdelta activators have been proposed for the treatment of metabolic disease. PPARgamma2 is expressed exclusively in adipose tissue and plays a pivotal role in adipocyte differentiation. PPARgamma is involved in glucose metabolism through the improvement of insulin sensitivity and represents a potential therapeutic target of type 2 diabetes. Thus PPARs are molecular targets for the development of drugs treating metabolic syndrome. However, PPARs also play a role in the regulation of cancer cell growth. Here, we review the function of PPARs in tumor growth.

Figure 1

The general features of human PPARs. (a) Structure and functional domain of human PPARs. A/B, C, D, and E/F indicate N-terminal A/B domain containing a ligand-independent activation function 1, DNA-binding domain (DBD), hinge region, and C-terminal ligand-binding domain (LBD), respectively. The number inside each domain corresponds to the percentage of amino acid sequence identity of human PPARδ and PPARγ relative to PPARα. (b) PPAR/RXR heterodimers bind to a PPRE located in the promoter of target genes through the DBD. Unliganded PPAR associates with the corepressor complex. In the presence of ligand, the ligand-bound LBD associates with the coactivator complex.

Figure 2

Does PPARδ progress or suppress tumor growth?