The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention

Abstract

Peroxisome proliferator-activated receptors (PPARs) have central roles in the regulation of glucose and lipid homeostasis through their functions as molecular sensors that respond to endogenous ligands, leading to the modulation of gene expression. PPARs also regulate cell proliferation, differentiation and inflammation. PPARα mediates hepatocarcinogenesis induced by long-term administration of PPARα agonists in rodent models, an effect that is not found in humans. The mechanism underlying species-specific hepatocarcinogenesis is through mouse PPARα-dependent regulation of the let-7c microRNA, which leads to increased expression of the oncoprotein MYC. The current interest in targeting PPARα for the prevention of certain cancers, including colon and leukaemia, is based on studies showing that PPARα agonists inhibit the proliferation of endothelial cells, increase the synthesis of PPARγ agonists and potentially interfere with the Warburg effect. The role of PPARβ/δ in carcinogenesis is controversial. Several studies have shown that PPARβ/δ is upregulated in cancer cells by the adenomatous polyposis coli (APC)–β-catenin–TCF4 pathway and has a pro-tumorigenic effect in many cancer types. However, other studies have shown that PPARβ/δ agonists can induce terminal differentiation and inhibit innate inflammation, suggesting anticancer effects. In addition, a retrospective study has shown that low expression levels of PPARβ/δ are associated with the decreased survival of patients with colorectal cancer. Therefore, there remains a need to further examine PPARβ/δ protein expression patterns quantitatively in tumour models and the putative mechanisms that are mediated by PPARβ/δ agonists associated with anti-apoptotic or growth stimulatory effects. PPARγ agonists can induce terminal differentiation, inhibit cell proliferation, promote apoptosis and inhibit innate inflammation in many cancer models. This has led to a number of clinical trials with PPARγ agonists, but these have generated mixed results. Moreover, some PPARγ agonists have been associated with pro-tumorigenic effects. Emerging evidence indicates that targeting PPARγ in combination with other chemopreventive or chemotherapeutic agents might increase the efficacy of the effects that are induced by monotherapies. Owing to similarities in the abilities of the three PPARs to improve different metabolic disorders that are known to be associated with increased cancer risk (such as diabetes, obesity, dyslipidemias and chronic inflammation), modulating the activities of the PPARs remains an attractive approach for the treatment and prevention of cancer. The challenge is to advance the discovery of molecular mechanisms of action in order to identify and characterize effective PPAR agonists with acceptable safety profiles.