Elsevier

The Lancet Oncology

Volume 5, Issue 7, July 2004, Pages 419-429
The Lancet Oncology

Review
Antineoplastic effects of peroxisome proliferatoractivated receptor γ agonists

https://doi.org/10.1016/S1470-2045(04)01509-8Get rights and content

Summary

Peroxisome proliferator-activated receptors (PPAR) are members of a superfamily of nuclear hormone receptors. Activation of PPAR isoforms elicits both antineoplastic and anti-inflammatory effects in several types of mammalian cells. PPARs are ligand-activated transcription factors and have a subfamily of three different isoforms: PPARα, PPARγ, and PPARβ/δ. All isoforms heterodimerise with the 9-cisretinoic acid receptor RXR, and play an important part in the regulation of several metabolic pathways, including lipid biosynthesis and glucose metabolism. Endogenous ligands of PPARγ include long-chain polyunsaturated fatty acids, eicosanoid derivates, and oxidised lipids. Newly developed synthetic ligands include thiazolidinediones—a group of potent PPARγ agonists and antidiabetic agents. Here, we review PPARγ-induced antineoplastic signalling pathways, and summarise the antineoplastic effects of PPARγ agonists in different cancer cell lines, animal models, and clinical trials.

Section snippets

The PPAR family

Nuclear hormone receptors are a large family of about 75 proteins in the mammalian proteome2 that enable the cell to respond to extracellular stimuli through transcriptional regulation of gene expression. The endogenous ligands of the PPAR subclass have not yet been fully defined. There are data to suggest that PPARs have an important role in the regulation of lipid homoeostasis and energy metabolism. At present, three isoforms have been identified and named PPARα, PPARβ/δ, and PPARγ. These

PPARγ and ligand interactions

Two PPARγ isoforms have been identified in mice and in people by use of alternative promoters and RNA splicing.4 The subtype PPARγ2 is different from PPARγ1 because it contains an additional 28 aminoacids at the amino terminus. Thus, the ligand-independent activation domain of PPARγ2 is five to ten times more effective than the ligand-independent activation domain of PPARγ1. Treatment of human adipocytes with insulin stimulates expression of PPARγ1 and PPARγ2. However, obesity and nutritional

Mechanisms of transcriptional transactivation

PPARγ forms a heterodimer with the RXR receptor—the common heterodimer partner for receptor complexes with thyroid hormone, retinoic acid, and colecalciferol (also called vitamin D3). The PPARγ/RXR heterodimer binds to sequence-specific PPAR response elements present in target genes10 and thereby acts as a transcriptional regulator (figure 2). PPAR response elements consist of a tandem hexameric TGACCT motif (called DR1) spaced by one nucleotide. This sequence has been identified in several

Proapoptotic mechanisms

PPARγ agonists induce apoptosis, which partly explains the antineoplastic effects of these agonists. In C6 glioma cells, Zander and co-workers23 described an upregulation of the proapoptoic proteins BAX and BAD and a functional role of BAX upregulation for the induction of apoptotic cell death. Upregulated expression of BAD and BAX causes apoptosis by the release of cytochrome C and subsequent activation of several effector caspases. In line with this hypothesis, PPARγ activation leads to

Prostate carcinoma

PPARγ is expressed in the healthy human prostate in low amounts. Mueller and colleagues45 found increased expression of PPARγ in cell lines obtained from human prostate carcinomas (LNCaP, DU145, PC3) and in human prostate adenocarcinomas (table 1). Several other studies have shown that PPARγ activation leads to inhibition of growth of prostate-cancer cell lines. This inhibition is accompanied by morphological changes such as prominent enlarged cytoplasmatic vacuoles, but not by signs of

Summary

Nearly 10 years has passed since the first PPAR subtype was identified. Since then, intense research has already led to the development of clinical approaches and of synthetic ligands, some of which are now in clinical use for treatment of type 2 diabetes. Several antineoplastic effects, such as induction of apoptosis and differentiation, have been described as a result of ligand binding to PPARγ both in vitro and in vivo.

The mechanisms by which the PPARγ agonists cause apoptosis of cancer

Search strategy and selection criteria

Data for this review were identified by searches of MEDLINE, PubMed, and references from relevant articles using the search terms “PPARgamma”, “cancer”, “apoptosis”, “cell cycle arrest”, “prostate cancer”, “thyroid cancer”, “gastric cancer”, “colon cancer”, “pancreatic cancer”, “hepatocellular cancer”, “breast cancer”, “lung cancer”, “neuroblastoma”, “astrocytoma”, and “glioma”. Abstracts and reports from meetings were included only when they directly related to previous published work. Only

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