Institut de Génétique et Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut Nationale de la Sauté et de la Recherche Médicale, Université Louis Pasteur, 67404 Illkirch, France
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ABSTRACT |
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The peroxisome
proliferator-activated receptor gamma (PPAR) has recently been
implicated in the pathogenesis of inflammatory bowel disease (IBD) and
colon cancer. The observation that PPAR
agonists, through immune
modulation, protect against inflammatory processes in the intestine
justified their expedient evaluation in the clinical management of IBD.
PPAR
agonists are reported to have both tumor-promoting and
-inhibiting effects in models of colon cancer. These differences can,
in part, be explained by PPAR
-independent effects of PPAR
agonists and by differences in the models used. Because it is still
unclear how PPAR
impacts on colon cancer, careful monitoring of
patients receiving PPAR
agonists and additional basic research is
indicated before recommendations on the use of PPAR
ligands in colon
cancer can be made.
cancer; inflammatory bowel disease; hepatitis; nuclear receptors; thiazolidinediones
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INTRODUCTION |
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THE PEROXISOME
PROLIFERATOR-ACTIVATED receptor (PPAR) is a nuclear
receptor that is activated by fatty acids and arachidonic acid
metabolites. Thiazolidinediones (TZDs), certain nonsteroidal anti-inflammatory drugs, L-tyrosine-based compounds, and
FMOC-L-leucine are the main classes of synthetic PPAR
ligands. PPAR
forms a heterodimer with the retinoic X receptor
(RXR), and this heterodimer is also permissive for activation by
RXR ligands. Ligand binding changes the conformation of the receptor,
enabling the recruitment of coactivators, and transcriptional
activation. PPAR
has classically been characterized for its
implications in adipocyte differentiation and metabolism. In addition
to adipose tissue, high levels of PPAR
are also found in the colon,
whereas stomach, small intestine, liver, and pancreas express lower but
still significant levels. PPAR
is mainly present in epithelial
cells, stellate cells, monocytes/macrophages, Kupffer cells, dendritic
cells, and B and T cells. In view of its expression and its involvement
in immune response and cell proliferation, PPAR
has become a hot
research topic in gastroenterology. This review provides a balanced
opinion on the role of PPAR
in two important gastrointestinal
disorders, i.e., inflammatory bowel disease (IBD) and colon cancer.
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PPAR![]() |
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PPAR not only controls the expression of genes involved in
differentiation but also negatively regulates the cell cycle. PPAR
activation reduces S phase entry by inhibiting E2F/DP DNA binding, by
inhibiting phosphorylation of the retinoblastoma protein, by inducing
the cyclin-dependent kinase inibitors p18 and p21, and by decreasing
cyclin D1 expression (reviewed in Ref. 4). TZDs induce the
tumor suppressor gene PTEN, which also contributes to their
antiproliferative activity. PPAR
activation inhibits the
proliferation of malignant cells, including those derived from
liposarcoma, breast adenocarcinoma, prostate carcinoma, colorectal carcinoma, nonsmall cell lung carcinoma, pancreatic carcinoma, bladder
cancer, and gastric carcinoma (reviewed in Ref. 4). This
growth inhibition is accompanied by changes in expression of genes
linked to growth regulation and cell maturation. In addition, in
adipocytes, macrophages, breast, prostate, and nonsmall cell lung
cancer cells, TZDs induce apoptosis (reviewed in Ref. 4).
Firm genetic evidence supporting an association or linkage between the
various polymorphisms/mutations in the PPAR gene and the occurrence
of cancer is at present lacking. Three studies tested whether somatic
mutations in the PPAR
gene were more frequent in cancers. In a first
study, four somatic mutations in the PPAR
gene were described in 55 sporadic colon cancers (26). Each of these mutations was
reported to reduce PPAR
function (26). In another
study, five of eight follicular thyroid carcinomas showed a fusion of
the DNA binding domains of the thyroid transcription factor PAX8 to
PPAR
(15). The PAX8-PPAR
fusion protein inhibited PPAR
in a dominant negative manner (15). The relevance
of these last two studies is, however, still unclear, because another
larger study failed to find any mutations in the PPAR
gene in
397 clinical cancer specimens of different origin (including colon,
prostate, breast, lung cancers, and leukemias) (13).
In vivo evidence to support an antitumorigenic role of PPAR is also
conflicting. PPAR
activation inhibited tumor growth and progression
in a xenograft model of prostate cancer (16), and
attenuated breast cancer induced either by nitrosomethylurea (29) or by 7,12-dimethylbenz[a]anthracene
(20). In vivo studies in colon cancer are particularly
relevant because prostaglandin products, which are generated by
cycloxygenase 2 (COX-2), are implicated in colon tumorigenesis and
PPAR
might simply function as a downstream mediator. Troglitazone
inhibited tumor growth in a xenograft model of colon cancer
(25) and reduced the formation of aberrant crypt foci
secondary to azoxymethane treatment (30). In sharp
contrast, two other studies demonstrated that activation of PPAR
promotes the development of colon tumors in
C57BL/6J-APCMin/+ mice (18,
24), a clinically relevant model for both human familial
adenomatous polyposis and sporadic colon cancer. A similar increase in
the frequency of colon tumors was also reported in mice on a high-fat
diet (32), suggesting that PPAR
could mediate the
effects of high-fat diet on colon cancer.
Also, clinical studies have not provided a conclusive answer on the
question whether PPAR activity is favoring or inhibiting cancer
formation and progression, because their outcome was largely deceiving
and the clinical benefits were rather limited. The best results were
obtained in three patients with liposarcoma, in which lineage-appropriate differentiation was induced (5).
Troglitazone also stabilized prostate-specific antigen (PSA) levels in
41 patients with advanced prostate cancer (21). This
effect on PSA levels was, in part, mediated by the inhibition of the
androgen receptor (12), hence the question of whether such
beneficial effects can be translated to other cancers that are
independent of androgen receptor activity.
Interestingly, a recent study also showed the involvement of PPAR in
the development of colorectal cancer (11). PPAR
, like
PPAR
, is expressed in the colon and can be activated by fatty acids.
PPAR
was shown to be a target gene for the
-catenin/Tcf-4 transcription complex, which is formed when the adenomatous polyposis coli (APC) tumor suppressor protein is mutated. In view of the coexpression of PPAR
and COX-2 (10), it was proposed
that PPAR
can mediate the protumorigenic effects of prostaglandins
in the colon, whereas nonsteroidal anti-inflammatory drugs were
suggested to inhibit tumorigenesis because they inhibit PPAR
activity (11). The lack of tumorigenicity of PPAR
/
human colorectal cells in nude mice supported a protumorigenic role of
PPAR
(23). At present, it is unclear how these
observations on PPAR
articulate with the involvement of PPAR
in
cell proliferation and colon cancer. Finally, it will be of interest to
evaluate whether mutations or modulation in expression of cofactors for
PPAR could influence PPAR-dependent tumor formation. A precedent for
such a role of cofactors was highlighted in estrogen receptor-dependent
breast cancers in which the coactivator, amplified in breast cancer-1, a member of the steroid receptor coactivator-1 family, or the nuclear
corepressor N-CoR (see Ref. 17) were mutated or downregulated (1,
17).
At present, not enough evidence is available to definitely establish
whether PPAR has pro- or antitumorigenic activities, and the field
remains confusing. A similar reflection needs to be made concerning
PPAR
. Some of this confusion is, however, secondary to the
differences in experimental design. First, the differentiation state of
the cells/tumors might affect the outcome. PPAR
activity is
influenced by numerous other factors (cofactors, mutations in genes
such as APC, differentiation status, etc.). For instance, PPAR
activation stimulated polyp formation (more well-differentiated
tissue), but implanted tumors were inhibited (less well-differentiated
tissue). A second difference, when considering animal models, stems
from the different nature of the models. In fact, the
C57BL/6J-APCMin/+ mice are more adequate to
study the spontaneous development of colon cancer, whereas the
xenograft model is better suited to analyze the behavior of a clonal
cancerous cell population. A final point is that the concentration of
PPAR
agonist used is important. In breast cancer cell lines, for
instance, low concentrations of PPAR
agonists induced cell
proliferation, whereas higher concentrations of the same agonists
correlate with cell cycle arrest and apoptosis (3). In
addition, high concentrations of PPAR
agonists elicit biological
effects that are independent of PPAR
activation. With the use of
PPAR
/
mouse embryonic stem cells, it was recently shown that
inhibition of cell proliferation by TZDs is independent of PPAR
and
mainly caused by blocking G1/S transition through inhibiting
translation initiation (inactivation of eIF2) (22). This
questions whether the antitumorigenic properties of TZDs can really be
attributed to activation of the receptor itself. A further point worth
stressing is the fact that the majority of antitumorigenic effects is
reported with troglitazone, a compound which has significant
antioxidant properties.
From all of the above, it is clear that PPAR's influence on cell
cycle proliferation, differentiation, and apoptosis is complex. These
effects depend on the concentrations of agonist, the cell type, and/or
the mutational events that predispose to cancer development. In the
absence of a full understanding of these mechanisms, careful monitoring
of Type 2 diabetes patients chronically treated with PPAR agonists in
postmarketing studies is indicated. Unfortunately, it will take several
years and thousands of patients before an eventual beneficial or
detrimental effect of TZDs on colon cancer formation will be unveiled
in such a clinical setting. In addition, these conflicting data dictate
the need of additional laboratory studies to address the role of
PPAR
in tumorigenesis.
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ROLE OF PPAR![]() |
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The molecular mechanisms mediating the anti-inflammatory action of
the PPAR/RXR heterodimer are, at present, not fully understood. Several studies have shown that activation of PPAR
may interfere with several signaling pathways regulating the expression of
proinflammatory genes, such as those controlled by the stress kinases,
nuclear factor-
B/Rel (NF-
B), signal transducers, and activators
of transcription (STATs), activating protein 1, and the nuclear factor
of activated T-cells (reviewed in Ref. 4). Consequent to
the inhibition of these signaling pathways, PPAR
activators modulate
the production of inflammatory cytokines, chemokines, and cell-adhesion
molecules, thereby limiting the recruitment of inflammatory cells
(reviewed in Ref. 4).
These anti-inflammatory effects, associated with the activation of the
RXR/PPAR heterodimer, incited several groups to explore their
involvement in gastrointestinal inflammatory disorders. Treatment with
TZDs has been shown to attenuate colitis induced either by oral
administration of dextran sodium sulfate (28, 30) or by
intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid
(TNBS) (6). This beneficial effect was directly attributed
to the RXR/PPAR
heterodimer, because it was reproduced by activation
of RXR with specific rexinoids (6). Further evidence in
support of the implication of the RXR/PPAR
heterodimer came from the
enhanced susceptibility to TNBS-induced colon inflammation of PPAR
+/
and RXR
+/
mice (6). The high expression of PPAR
in epithelial cells suggests that these cells constitute the
main target of the RXR/PPAR
activators, a hypothesis reinforced by
the persistence of inflammation in deeper layers of the colon in
animals treated with PPAR
and/or RXR agonists (6).
Despite evidence for anti-inflammatory actions of the RXR/PPAR
heterodimer in the colon in animal models, the role of PPAR
in
ulcerative colitis (UC) and Crohn's disease (CD), the two main forms
of IBD in humans is little explored. In patients with UC, we recently
observed an impaired expression of PPAR
at the mRNA and protein
levels (P. Desreumaux and J. Auwerx, unpublished data). As
peripheral mononuclear cells of UC patients expressed normal levels of
PPAR
, it is likely that factors within the intestinal lumen may
contribute to the observed decreased expression of PPAR
in
epithelial cells. CD, on the other hand, is characterized by a
localized hypertrophy of mesenteric adipose tissue, resulting in the
so-called fat wrapping of the intestine (7). This
hypertrophic mesenteric adipose tissue in CD is a rich source of tumor
necrosis factor
(TNF
), which sustains local inflammatory
responses (7). On the basis of the above information,
several clinical trials have been initiated to evaluate the therapeutic
efficacy of PPAR
agonists in IBD.
In addition, recent studies hint to eventual potential roles of PPAR
in other gastrointestinal disorders. In gastric epithelial cells,
PPAR
activation was shown to be involved in the suppression of
NF-
B-mediated apoptosis induced by
Helicobacter pylori, suggesting eventual medical
applications in gastroduodenal pathologies (9). Furthermore, PPAR
is expressed in hepatoma cell lines
(14), Kupffer cells (31), and hepatic
stellate cells (HSC) (8, 19), indicating a potential role
in the liver. Most literature concerning PPAR
in the liver, however,
relates to the hepatotoxicity of troglitazone, a problem that is much
rarer with other TZDs (27). The two liver pathologies in
which some preliminary evidence exists for the involvement of PPAR
are fibrosis and nonalcoholic steatohepatitis (NASH). In rat Kupffer
cells, both PPAR
and RXR agonists inhibit lipopolysaccharide-induced
nitric oxide and TNF
production (31). Likewise,
activation of the RXR/PPAR
pathway has anti-inflammatory effects on
HSC, in which they are reported to block proliferation
(8), migration, and production of the chemokine MCP-1
(19). Because HSC are the main collagen-producing cells in
the liver and because MCP-1 expression is directly related to
recruitment of inflammatory cells to the liver, these data suggest that
RXR/PPAR
may represent a therapeutic target for liver inflammation
and fibrosis. PPAR
has also been suggested to be involved in the
pathophysiology of fatty liver diseases, because it is highly expressed
in the liver of genetically obese animals. NASH, a complex
multifactorial disease often associated with obesity, Type 2 diabetes,
and hypertriglyceridemia, recapitulates certain aspects of the liver
pathology seen in these animal models. Although often silent, NASH
progresses to cirrhosis in ± 5-15% of patients.
Administration of troglitazone has been reported to induce
normalization of liver enzymes with histological improvement in 7 of 10 patients enrolled in a small pilot study (2).
In conclusion, PPAR evolved quickly from a nuclear receptor
controlling metabolism to a pleiotropic regulatory factor, which affects numerous processes ranging from carcinogenesis to inflammation. At present, it is not yet clear whether PPAR
activation favors, or
rather inhibits, colon tumorigenesis. Pharmacological studies using
PPAR
ligands are compromised of PPAR
-independent effects of these
compounds, confounding the interpretation of results. Human genetic
studies and studies using gain and/or loss of function mouse models are
not plagued by these confounding factors and will be required to
unequivocally establish a role of PPAR
in colon neoplasia. Until
these issues are adequately addressed, careful clinical monitoring of
patients treated with TZDs will be required to detect potential effects
on colon cancer incidence. Furthermore, it is premature to advocate the
use of PPAR
agonist, antagonists, or modulators in neoplastic syndromes.
Current scientific evidence, derived from a combination of
pharmacological and genetic studies, provides solid evidence for the
involvement of the RXR/PPAR in the control of gastrointestinal inflammation. This seems to justify the thorough clinical evaluation of
RXR and PPAR
activators, either alone or in combination, as new
anti-inflammatory drugs. Potential clinical applications could extend
beyond the two common forms of IBD (UC and CD) to include inflammatory
syndromes in the upper gastrointestinal tract and liver. In the future,
it is expected that the better understanding of how RXR/PPAR
affects
transcriptional control will guide the development of selective
modulators of this heterodimer, which are specifically targeted to the
digestive tract and would avoid side effects in other organs.
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ACKNOWLEDGEMENTS |
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Work in the laboratory of the author is supported by grants of Centre National de la Recherche Scientifique, Institut Nationale de la Sauté et de la Recherche Medicale, Hopitaux Universitaires de Strasbourg, Association pour la Recherche center le Cancer, the European Community, the National Institutes of Health, the Human Frontier Science Program, and Association Régionale pour l'Euseiguement et la Recherche Scientifique.
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FOOTNOTES |
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Due to the limited number of references allowed for themes articles not
all work related to PPAR and the gastrointestional tract is cited.
Interested readers can obtain a complete list from the author.
Address for reprint requests and other correspondence: J. Auwerx, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 Rue Laurent Fries, 67404 Illkirch, France (E-mail: auwerx{at}igbmc.u-strasbg.fr).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpgi.00508.2001
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