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Peroxisome-proliferator-activated receptors and cancers: complex stories

Nature Reviews Cancer volume 4, pages 61–70 (2004)Cite this article

Key Points

  • Peroxisome-proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear-hormone-receptor family. Three isotypes have been identified — PPARα, PPARβ/δ and PPARγ.

  • PPARs are activated by endogenous ligands — fatty acids and fatty-acid derivatives, for which they act as intracellular sensors — which leads to transcriptional regulation of pathways that are involved in lipid and glucose metabolism.

  • PPARα is the therapeutic target of the fibrates, which are widely used as hypolipidaemic compounds in the treatment of dyslipidaemia. PPARγ is a non-exclusive target of the thiazolidinediones, a new class of compounds with hypoglycaemic properties that are used to treat type II diabetes. Because of its involvement in lipid metabolism and skin homeostasis, it is likely that PPARβ/δ will become a therapeutic target in the near future.

  • Each PPAR isotype is associated with pathways that relate to carcinogenesis. Long-term activation of PPARα by peroxisome proliferators induces the development of hepatocarcinomas in rodent liver, but not in humans. PPARγ is thought to have overall anti-carcinogenic effects in many different cell types, due to its anti-proliferation, pro-differentiation and pro-apoptotic properties. PPARβ/δ is involved in the control of cell proliferation, cell differentiation and apoptosis, but its involvement in the development of tumours is unclear at present.

  • In the future, PPARγ, and perhaps PPARβ/δ, might become interesting therapeutic targets for the treatment of tumours. However, further investigation is needed at both the scientific and clinical levels.

Abstract

Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors that mediate the effects of fatty acids and their derivatives at the transcriptional level. Through these pathways, PPARs can regulate cell proliferation, differentiation and survival, so controlling carcinogenesis in various tissues. But what are the links between each PPAR isotype and carcinogenesis and what is the relevance of these findings to human pathology and therapy?

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Figure 1: Schematic representation of the PPAR signalling pathways.
Figure 2: Consequences of Pparα activation by PP in the liver and proposed underlying mechanisms.
Figure 3: PPARβ/δ and PPARγ functions that relate to their carcinogenic properties.

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Acknowledgements

The authors wish to thank L. Gelman for critical reading of this manuscript. The work done in the authors' laboratory was supported by the Swiss National Science Foundation (grants to W.W. and to B.D.), the Etat de Vaud and the Human Frontier Science Program Organization.

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  1. Center for Integrative Genomics, NCCR Frontiers in Genetics, University of Lausanne, Lausanne, CH-1015, Switzerland

    Liliane Michalik, Béatrice Desvergne & Walter Wahli

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  1. Liliane Michalik
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  2. Béatrice Desvergne
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  3. Walter Wahli
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Correspondence to Walter Wahli.

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DATABASES

Cancer.gov

breast cancer

colon cancer

endometrial cancer

head and neck cancer

non-small-cell lung cancer

prostate cancer

thyroid cancer

LocusLink

AKT1

Apc

β-catenin

cyclin D1

GADD153

ILK

INK4C

keratin 20

NF-κB

PDK1

Pgi2

PPARα

PPARβ/δ

PPARγ

PTEN

Rb

RXR

TSC22

WAF1

OMIM

familial adenomatous polyposis

Glossary

PEROXISOMES

Organelles that are found in all organisms and in various cell types. They are involved in many different functions, among which β-oxidation of long-chain fatty acids and H2O2-based respiration are the most prominent.

LIPOXYGENASES

5-, 12-, and 15-lipoxygenases are enzymes that catalyse a key step in the production of leukotrienes in platelets, macrophages, mastocytoma cells and leukocytes.

CYCLOOXYGENASES

(COXs). These catalyse a key step in the conversion of 20-carbon polyunsaturated fatty acids — such as arachidonic acid — to prostaglandins. COX1 is constitutively expressed in most tissues, but COX2 is induced by pathophysiological conditions such as tumorigenesis or inflammatory situations. COX2 is now recognized as an interesting target for the treatment of cancers.

LIPOPROTEIN

Association of proteins with triglycerides, phospholipids and cholesterol. Lipoproteins are produced in the liver and serve as lipid carriers in the blood.

KERATINOCYTE

The main cell type of the epidermis, the uppermost layer of the skin. Basal keratinocytes are responsible for the renewal of the epidermis. The daughter keratinocytes then undergo a vectorial specific differentiation programme, while migrating to the top of the epidermis, where they finally die and desquamate.

DYSLIPIDAEMIAS

The term lipidaemia refers to the circulating level of total lipids, including free fatty acids and lipoproteins. Dyslipidaemias are pathological disorders that affect normal lipidaemia, usually corresponding to high blood lipid levels that are a high risk factor for cardiovascular diseases.

COLITIS

Inflammatory state of the colon, possibly due to a single cause such as bacterial infection.

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Michalik, L., Desvergne, B. & Wahli, W. Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat Rev Cancer 4, 61–70 (2004). https://doi.org/10.1038/nrc1254

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