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Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors originally identified as molecular targets of synthetic compounds inducing peroxisome proliferation. As ligand-dependent transcription factors, PPARs mediate the effects of fatty acids and their derivatives and thereby regulate proliferation, differentiation, and cell survival.
The three peroxisome proliferator-activated receptor isoforms, PPARα, PPARβ/δ, and PPARγ, are encoded by different genes and belong to the largest family of transcription factors, the nuclear hormone receptors (NHRs).
PPARs possess a modular structure composed of a central DNA-binding domain (DBD) with two zinc fingers and a ligand-binding domain (LBD), including the ligand-binding pocket and the ligand-dependent activation domain AF-2 in its C terminus (Fig. 1). A ligand-independent, poorly characterized transactivation function at the N terminus is known as AF-1. PPARs control gene expression by binding to specific PPAR response elements (PPREs) corresponding to the consensus motif 50-AACT AGGNCA A AGGTCA-30typically located in the promoters of their target genes. Like many other NHRs, PPARs bind DNA as obligatory heterodimers by interacting with one of the retinoid acid receptors (RXRs). In the unliganded form, PPAR-RXR dimers can actively silence gene expression by recruiting corepressor complexes. Conformational changes upon ligand binding promote interaction with coactivators such as p300/CBP, leading to transcriptional activation of PPAR target genes (Fig. 2). Endogenous ligands are fatty acids and their derivatives, for which PPARs act as intracellular sensors and thereby regulate pathways involved in lipid and glucose metabolism. Correspondingly, synthetic PPAR ligands such as fibrates and thiazolidinediones (TZDs) are used for the treatment of dyslipidemia and type II diabetes, respectively. Besides their role in metabolism, PPAR functions are also associated with other processes of clinical importance, such as arteriosclerosis, inflammation, and especially cancerogenesis.
PPARα is expressed in the liver, kidney, heart, intestine, skeletal muscle, brown fat tissue, adrenal gland, and pancreas. It was the first PPAR family member identified in a screen for molecular targets of peroxisome proliferators (PPs) using a mouse liver cDNA library. PPs are livertargeting chemically unrelated compounds, including natural lipids and steroids as well as xenobiotics, industrial plasticizers, pesticides, and solvents. Chronic PP administration in rodents leads to liver hypertrophy, to hyperplasia, and eventually to hepatocellular carcinoma. The exclusive role of PPARα in mediating these processes was deduced from PPARα-null mice that are resistant to the effects of PP treatment, including the development of hepatocellular carcinomas. The exact mechanisms underlying the tumorigenic PPARα function are unclear, but several explanations have been proposed: PP-activated PPARα triggers DNA replication and proliferation of hepatocytes, accompanied by an induction of cell cycle regulators such as cyclin-dependent kinases CDK-1 and CDK-2 as well as c-MYC. Further, PPs attenuate hepatocytic apoptosis in vitro and in vivo. PPARα appears to be critical to this effect since inhibition of apoptosis can be prevented by a dominant-negative PPARα protein. Another PPARα-mediated mechanism reported is the production of reactive oxygen species as by-products of b-oxidation, possibly leading to DNA damage and increased proliferation of hepatocytes. Despite the clear evidence for PPARα- mediated PP action in rodent hepatocarcinogenesis, the situation in humans appears to be different. Studies did not reveal activated peroxisome proliferation in the liver or any increased incidence of hepatocellular carcinoma in patients treated with hypolipidemic fibrate drugs. Consistently, in vitro experiments with human cells showed a reduced transcriptional response to activated PPARα compared with rodents. A lower level of hepatocytic PPARα expression (1–10 %), different cofactor availabilities and PPREs of target genes, as well as a reduced activation efficiency and bioavailability of certain PPs are discussed as possible explanations for these species differences. Nevertheless, as many humans are constantly exposed to PPs (e.g., hypolipidemic drugs, pesticides, plasticizers), it is very important to constantly resurvey the cancerogenic potential of these compounds.
PPARβ/δ (NUC1, FAAR)
PPARβ/δ is expressed in a wide range of tissues with high levels in the brain, skin, adipose tissue, and colon. Although the role of PPARβ/δ in cancer is controversial, its involvement in processes related to tumorigenesis such as proliferation, differentiation, and survival is well accepted. For example, a role for PPARβ/δ in the differentiation of adipose tissue and oligodendrocytes was concluded from the phenotype of PPARβ/δ-null mice, exhibiting a decreased fat mass and myelination defects in the corpus callosum, respectively. In keratinocytes, PPARβ/δ inhibits proliferation but promotes cell migration and survival via activation of ILK, PDK1, and AKT1. A role for PPARβ/δ as a mediator of proliferation in hepatic stellate cells and vascular smooth-muscle cells has been reported. The strongest link to cancerogenesis has been demonstrated in murine colorectal cancer cells, where PPARβ/δ expression is repressed by the APC/β-catenin tumor-suppressor pathway. Aside from the APC pathway, PPARβ/δ is also targeted by theRas pathway, as it becomes activated in response to an overexpression of oncogenic Kras. For both pathways, regulation of cyclooxygenase 2 (COX2) levels might be the underlying mechanism, as COX2 is the ratelimiting factor in the generation of some natural PPARβ/δ ligands (prostaglandins). PPARβ/δ activation in human hepatocellular carcinoma cells increases proliferation and COX2 expression, suggesting a growth-promoting positive feedback loop. Consistent with a direct role in colorectal tumorigenesis, PPARβ/δ-/- colon cancer cells show a significantly decreased tumorigenic potential in xenograft mouse models. Moreover, PPARβ/δ upregulates VEGF in colon carcinoma cells, which directly promotes colon tumor epithelial cell survival through activation of PI3K-AKT signaling. The repression of PPARβ/δ activity by the nonsteroidal anti-inflammatory drug (NSAID) sulindac might explain NSAID-mediated chemoprevention of colon cancer. The role of PPARβ/δ in tumors other than colon cancer is far from being clear. Significant upregulation of PPARβ/δ has been observed in head and neck squamous cell carcinomas, endometrial adenocarcinomas, and breast cancer cell lines. A growth-inhibiting activity of PPARβ/δ has been suggested in lung cancer cells. In summary, pro- and anti-cancerogenic PPARβ/δ functions seem to exist, depending on the cell- and tissue-specific context.
PPARγ exists as two protein isoforms, expressed from different promoters and alternatively spliced at the 50end of the gene, resulting in 30 additional amino acids at the NH2 terminus of PPARγ2 compared with PPARγ1. Whereas expression of PPARγ2 is mainly restricted to adipose tissue, PPARγ1 has also been detected in other tissues, including the heart, skeletal muscle, pituitary, brain, kidney, liver, and colon. The concept of PPARγ playing a role in tumorigenesis and therefore being a potential target in cancer therapy was developed from its antiproliferative activity in fibroblasts during adipogenesis. Also in other cell types, PPARγ activation induces programs of gene expression that reflect the differentiation potential of progenitor cells. For instance, its expression in epithelium-derived cells stimulates the production of markers of epithelial differentiation/maturation, such as keratin 20 and Krüppel-like factor 4. Additionally, PPARγ inhibits cell proliferation through induction of cyclin-dependent kinase inhibitors (i.e., p21 and p18Ink4c) and attenuates E2F/DP DNA-binding activity via downregulation of PP2A protein phosphatase. Consistent with an integrating role coupling cell differentiation and growth arrest, loss of one allele of PPARγ predisposes to carcinogenesis in wild-type mice, while loss-of-function mutations in PPARγ associate with human colon cancer. Additional evidence for the impact of PPARγ on tumorigenic processes comes from the identification of a chromosomal translocation in a subset of follicular thyroid carcinomas, resulting in a PAX8-PPARγ fusion protein which abolishes the ligand activation of the wild-type PPARγ protein. Building up on these findings, intense clinical interest has been raised in the possible application of synthetic PPARγ ligands as effective chemotherapeutic agents. Indeed, PPARγ ligands have been shown in vitro to induce cell cycle arrest and/or apoptosis in a variety of cancer cell types, including liposarcoma, breast adenocarcinoma, prostate carcinoma, neuroblastoma, pancreas, and colon carcinoma cells. However, the role of PPARγ ligands – which have also PPARγ-independent effects – in the regulation of neoplastic transformation in vivo remains controversial. In contrast to the reduction of aberrant crypt foci and the inhibition of colon cancer growth in wild-type mice, PPARγ ligands in APCMin mice not only failed to suppress polyp formation but also led to a small although significant increase in colon tumors. Moreover, epidemiological data emphasize that the development of colorectal cancer is promoted by prostaglandins, which are potential ligands of PPARγ. In mice with mutations in the cyclooxygenase gene or in animals and humans treated with COX inhibitors, decreased production of prostaglandins prevents or attenuates colon cancer development. Furthermore, the intake of fatty acids from animal origins strongly correlates with colon tumors, suggesting that PPARγ possibly links high-fat diet and colon cancer. Studies aimed to find an explanation for the contradictory results with PPARγ in colon cancer revealed that the tumor-suppressor function of PPARγ entirely depends on the presence of an intact adenomatous polyposis coli (APC) gene. The cross-regulation of Wnt/β-catenin/Tcf ligands, kinases, and transcription factors with members of the nuclear receptor family has emerged as clinically and developmentally important area of endocrine cell biology. Wnt/ββ-catenin can modulate NR activity, and NR ligand dependently inhibits the Wnt/β-catenin/Tcf cascade. As a case in point, PPARγ can suppress β-catenin levels in wildtype mice, whereas in the presence of a mutant APC, the ability of PPARγ to regulate β-catenin and colon tumorigenesis is completely lost. In normal cells, PPARγ targets β-catenin to the proteasome partly through a process possibly involving PPARγ induction of PTEN and activation of the downstream effector GSK3-β. b-Catenin and PPARγ interact with each other through the TCF/LEF binding domain of β-catenin and the putative coactivator binding sites of PPARγ to influence each other’s activity. As a result, in normal untransformed cells, PPARγ additionally induces the proteasomal degradation of β-catenin through complex formation independent from GSK3-β, while in transformed cells, oncogenic β-catenin escapes its PPARγ-associated degradation and inhibits in turn PPARγ activity. In this model, the oncogenic form of β-catenin is dominant over PPARγ activity, thus explaining why PPARγ is capable of suppressing tumorigenesis only in cells that have a functional APC to facilitate the GSK3-β-mediated inactivation of β-catenin. As a further indication for a role of PPARγ in suppressing the oncogenic activity of β-catenin, NSAIDs have been reported to antagonize β-catenin function via high levels of PPARγ and its co-receptor RXR-a, which is independent from the presumed role of NSAIDs in COX inhibition. Finally, epidemiological studies demonstrate long-term ingestion of various NSAIDs to associate with a reduced incidence of colorectal cancer and probably of prostate and breast tumors. Taken together, the multilayered and cell type-specific activity of PPARγ and its interconnection with the Wnt/β-catenin/Tcf pathway argue against the indiscriminately and broad use of PPARγ ligands in cancer treatment. Thus, despite the substantial progress being made in the understanding of the role of PPARγ in cancerogenesis during the last decade, further investigations appear necessary to elucidate and refine indications for a PPARγ-targeted therapy.
Fig. 1. The PPAR receptor family. Human PPARs share a common modular structure typical for the nuclear receptor superfamily. The highly conserved central DNA-binding domain (DBD) contains two variant zinc fingers. By each of them, one zinc ion is bound by a tetrahedral arrangement of cysteine ligands. The C-terminal ligand-binding domain (LBD) and the ligand-independent and ligand-dependent activation domains (AF-1 and AF-2, respectively) are less conserved and confer transcription regulation via their interaction with coactivator and corepressor complexes. Amino acid numbers are indicated for each receptor isoform
Fig. 2. Transcriptional activity of PPAR-RXR heterodimers. Left, in the unliganded state, PPAR-RXR heterodimers bind to PPREs in the promoter region of target genes and inhibit their transcription by recruiting corepressors (Co-Rep). Right, upon ligand (L) binding, corepressors are released and coactivators (Co-Act) such as p300/CBP are recruited to cooperatively activate transcription of PPAR target genes
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