Peroxisome proliferator-activated receptors and cancer: challenges and opportunities

Abstract

Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor superfamily, function as transcription factors and modulators of gene expression. These actions allow PPARs to regulate a variety of biological processes and to play a significant role in several diseases and conditions. The current literature describes frequently opposing and paradoxical roles for the three PPAR isotypes, PPARα, PPARβ/δ and PPARγ, in cancer. While some studies have implicated PPARs in the promotion and development of cancer, others, in contrast, have presented evidence for a protective role for these receptors against cancer. In some tissues, the expression level of these receptors and/or their activation correlates with a positive outcome against cancer, while, in other tissue types, their expression and activation have the opposite effect. These disparate findings raise the possibility of (i) PPAR receptor-independent effects, including effects on receptors other than PPARs by the utilized ligands; (ii) cancer stage-specific effect; and/or (iii) differences in essential ligand-related pharmacokinetic considerations. In this review, we highlight the latest available studies on the role of the various PPAR isotypes in cancer in several major organs and present challenges as well as promising opportunities in the field.

Figure 1

Functional domains of mouse PPARα, PPARβ/δ and PPARγ. PPAR, peroxisome proliferator-activated receptor.

Figure 2

Chemical structures of representative PPAR agonists. PPARα, WY 14643; PPARβ/δ, L-165041; PPARγ, rosiglitazone. PPAR, peroxisome proliferator-activated receptor.

Figure 3

Transcription regulation of target genes by PPARs [reproduced from Shimizu and Moriwaki (2008) with permission from Dr Masahito Shimizu]. PPAR, peroxisome proliferator-activated receptor; PPRE, PPAR response element; RXR, retinoid X receptors.

Figure 4

Mechanism of action of PPARγ ligands in hematological malignancies [reproduced from Garcia-Bates et al. (2008) with permission from Dr Richard Phipps]. PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptors.

Figure 5

Potential role of PPARγ, fatty acid ligands, adipose tissue and the plasminogen activator system in breast cancer [reproduced from Carter and Church (2009) with permission from Dr Frank C. Church]. PPAR, peroxisome proliferator-activated receptor.

Figure 6

A hypothetical schematic representation of the synergistic anti-cancer effects of the combination of PPAR ligands plus other agents [reproduced from Shimizu and Moriwaki (2008) with permission from Dr Masahito Shimizu]. PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptors.

Figure 7

A schematic representation depicting a hypothesis explaining the paradoxical, anti-carcinogenic/pro-carcinogenic, effect of PPAR agonists. COX-2, cyclooxygenase-2; PPAR, peroxisome proliferator-activated receptor.