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

Nature Reviews Cancer volume 12, pages 181–195 (2012)Cite this article

Subjects

Key Points

  • 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.

Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention. As PPAR agonists include drugs that are used for the treatment of metabolic diseases, a more complete understanding of the roles of PPARs in cancer will aid in determining any increased cancer risk for patients undergoing therapy with PPAR agonists.

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Figure 1: Molecular regulation of transcription by PPARs.
Figure 2: Physiological roles of PPARs.
Figure 3: Contrasting mechanisms of PPARβ/δ in cancer.
Figure 4: Targeting PPARγ for the prevention and treatment of cancer.
Figure 5: Potential targeting of PPARα for prevention and treatment of cancer.

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Acknowledgements

The authors gratefully acknowledge J. Corell for technical assistance with the figures and P. Devchand for critical review and suggestions for the manuscript. The authors' research is supported by the US National Institutes of Health (CA124533, CA126826, CA141029, CA140369 and AA018863) to J.M.P., (R01CA148828) to Y.M.S. and the National Cancer Institute Intramural Research Program (ZIABC005561, ZIABC005562 and ZIABC005708) to F.J.G.

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Authors and Affiliations

  1. Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, 16802, Pennsylvania, USA

    Jeffrey M. Peters

  2. Department of Molecular and Integrative Physiology, Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Yatrik M. Shah

  3. Laboratory of Metabolism, National Cancer Institute, Bethesda, 20892, Maryland, USA

    Frank J. Gonzalez

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Glossary

Peroxisome proliferator-activated receptors

(PPARs). This class of nuclear receptor acquired their name because the first receptor of this class identified (PPARα) mediates the phenomenon of the proliferation of peroxisomes observed in rodents given fibrates and other chemicals.

Agonists

Compounds that bind to a receptor that invokes a biological response that is most often transcriptionally mediated. The specificity of an agonist is often defined by its ability to bind to the receptor at a given concentration and whether it is able to interact with a single receptor.

Chemoprevention

The inhibition or prevention of disease by use of a drug or natural compound. Many chemopreventive agents show anti-inflammatory activities.

Antagonists

Compounds that bind to a receptor and that block all known receptor activities induced by activation by an agonist. The potency of an antagonist is often defined by the concentration required to inhibit activation by an agonist.

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Peters, J., Shah, Y. & Gonzalez, F. The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Rev Cancer 12, 181–195 (2012). https://doi.org/10.1038/nrc3214

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