<title>1. INTRODUCTION</title> <p>Peroxisome proliferator-activated receptors (PPARs) are ligand-activated
nuclear receptors that function as transcription
factors regulating the expression of genes involved in lipid biosynthesis, glucose
metabolism, as well as cell proliferation, differentiation, and survival [##REF##16476485##1##–##REF##11729302##4##]. Their
discovery was driven by search of a molecular target for peroxisome
proliferators, a group of agents named after their property to increase
peroxisomes in rodent liver [##REF##2129546##5##, ##UREF##0##6##]. Later on, activity studies helped elucidate
the versatile role of these molecules in modulating diverse biological
functions such as metabolism, tissue remodeling, inflammation, angiogenesis,
and carcinogenesis [##REF##10839530##7##–##UREF##2##11##]. Three
PPAR gene types have been identified: <italic>α</italic>, <italic>β</italic>/<italic>δ</italic>, and <italic>γ</italic> [##REF##10022237##12##, ##REF##12059785##13##]. Between them,
PPAR<italic>γ</italic> is the most intensively investigated [##UREF##3##14##, ##REF##16360030##15##].</p>
<title>5. CONCLUSION</title> <p>Existing
data suggest that peroxisome proliferator-activated receptor-gamma (PPAR<italic>γ</italic>) is a
potential target ally to cancer chemopreventive agents. Although PPAR<italic>γ</italic> was first understood as a key
regulator of adipocyte differentiation and glucose homeostasis, it is now
recognized that it
is also involved in cell proliferation, differentiation, apoptosis, and
angiogenesis. Meticulous research for PPAR<italic>γ</italic> agonists with potency to function as cancer
chemopreventive agents is highly warranted.</p>
<p>Recommended by Dipak Panigrahy</p> <p>Peroxisome proliferator-activated receptor-gamma (PPAR<italic>γ</italic>), one of three ligand-activated transcription factors named PPAR, has been identified as a molecular target for cancer chemopreventive agents. PPAR<italic>γ</italic> was initially understood as a regulator of adipocyte differentiation and glucose homeostasis while later on, it became evident that it is also involved in cell differentiation, apoptosis, and angiogenesis, biological processes which are deregulated in cancer. It is now established that PPAR<italic>γ</italic> ligands can induce cell differentiation and yield early antineoplastic effects in several tumor types. Moreover, several bioactive natural products with cancer protecting potential are shown to operate through activation of PPAR<italic>γ</italic>. Overall, PPAR<italic>γ</italic> appears to be a prevalent target ally to cancer chemopreventive agents and therefore pursuing research in this area is of great relevance.</p>
<title>2. THE HUMAN PPAR<italic>γ</italic> GENE</title> <p>The human PPAR<italic>γ</italic> gene consists of six coding exons located at chromosome 3p25.2 and
extends approximately over 100 kb of genomic DNA [##REF##9168928##16##]. 
Three major transcriptional
start sites have identified where three mature mRNAs originate from, differing
in their 5′ untranslated regions 
[##REF##9228052##17##, ##REF##9821958##18##]. Notably PPAR<italic>γ</italic>1 and
PPAR<italic>γ</italic>3 mRNAs code for the same protein of 475 amino
acids, while PPAR<italic>γ</italic>2 transcript codes for a different protein
which contains an additional 28 N-terminal amino acids [##REF##7926726##19##].</p> <title>2.1. Tissue
distribution of different PPAR<italic>γ</italic> isoforms</title> <p>The PPAR<italic>γ</italic>1 is found in virtually all tissues, such as liver, skeletal
muscle, prostate, kidney, breast, intestine, and the gonads. The PPAR<italic>γ</italic>2 is the
major PPAR<italic>γ</italic> isoform expressed mainly in adipose tissue where it normally operates as
an adipocyte-specific
transcription factor in preadipocytes and regulates
adipose tissue differentiation, and the PPAR<italic>γ</italic>3 isoform is restricted to adipose
tissue and large intestine [##REF##9821958##18##, ##REF##9065481##20##],</p> <title>2.2. PPAR<italic>γ</italic> protein structure and function</title> <p>Similar to other members of the nuclear hormone receptors superfamily,
PPAR<italic>γ</italic> protein has three functional domains: the N-terminal domain, the DNA-binding
domain, and a carboxy-terminal ligand-binding pocket 
(##FIG##0##Figure 1##).</p> <p>PPAR<italic>γ</italic> protein receptor is activated by a number of endogenous and exogenous
ligands of various potencies. Among pharmaceutical compounds, thiazolidinedione
(TZD) class of insulin-sensitizing drugs (also called glitazones) are best
known to operate as ligands to PPAR<italic>γ</italic> [##REF##9744270##21##, ##REF##9813012##22##] while long-chain
polyunsaturated fatty acids are the most well-characterized endogenous ligands [##REF##8240670##23##].</p> <p>The activated PPAR<italic>γ</italic>
protein becomes operational following its heterodimerization with retinoid X
receptors (RXR) [##REF##1324435##24##]. The PPAR<italic>γ</italic>/RXR complex translocates to the nucleus where it binds to target genes
which contain a peroxisome proliferator response element (PPRE). A PPRE consist of a direct repetition of the
consensus sequence AGGTCA separated by a single nucleotide (Direct repetition; DR1) [##REF##9228052##17##]. To initiate transcriptional regulation of PPRE-bearing
genes, the PPAR<italic>γ</italic>/RXR complex requires accessory
proteins to bind on. These proteins can
either trigger (coactivators) or represses gene transcription (corepressors) 
(##FIG##0##Figure 1##). It must be noted though that besides their PPAR<italic>γ</italic>-dependent genomic effects, PPAR<italic>γ</italic> ligands can also influence
cellular biology via nongenomic, PPAR<italic>γ</italic>-independent events [##REF##17611413##25##] 
(##FIG##0##Figure 1##).</p> <p>As a rule, the
transcriptional activity of PPAR<italic>γ</italic> is negatively
modulated through phosphorylation by MAPK [##REF##8953045##26##–##REF##17560826##28##]. Phosphorylation of human PPAR<italic>γ</italic>1 protein at Ser-84 site
restrains its function [##REF##9030579##27##], and
phosphorylation of PPAR<italic>γ</italic>2 modifies the A/B domain and reduces its ligand binding affinity [##REF##9845075##29##]. However,
not all phosphorylation events are inhibitory. For example, it has been found
that missense mutation which results in the conversion of proline to glutamine
at position 115 can render PPAR<italic>γ</italic>2 constitutively active through modulation of the
MAPK-dependent phosphorylation status of serine 114 [##REF##9753710##30##] while
phosphorylation by protein kinase A (PKA) was shown to enhance its activity [##REF##11117527##31##].</p> <p>Until now, three molecular processes have been
proposed for the termination and downregulation of PPAR<italic>γ</italic> signaling: the phosphorylation of Ser-84/112 of PPAR<italic>γ</italic>1/2 by ERKs [##REF##9030579##27##], the
proteasomal degradation of ligand-activated PPAR<italic>γ</italic> [##REF##11733495##32##], and the interaction with MEKs, which promotes its expulsion
from the nucleus [##REF##17101779##33##].</p> <title>3. PPAR<italic>γ</italic> IN CANCER</title> <p>Early studies portrayed
PPAR<italic>γ</italic> as an important regulator of preadipocyte
differentiation and glucose homeostasis. Later on, it was identified that PPAR<italic>γ</italic> 
regulates biological processes which are considered
hallmarks of cancer such as cell differentiation, apoptosis, and angiogenesis. This
knowledge, coupled with data showing that PPAR<italic>γ</italic> ligands could yield anticancer
effects in several cell types, led researches postulate a role for PPAR<italic>γ</italic> in carcinogenesis [##UREF##2##11##, ##REF##14708026##34##, ##REF##16887936##35##].</p> <p>Apoptosis is
believed to be a fundamental molecular mechanism through which PPAR<italic>γ</italic> activators
exert their action against cells which undergo malignant transformation [##REF##17911009##36##–##REF##17582756##38##]. Moreover, apart from their direct inhibitory
effects on cancerous transformed cells, PPAR<italic>γ</italic> can also inhibit angiogenesis
which is a prerequisite for tumor formation and growth [##REF##17396134##39##–##REF##16082179##41##]. It is suggested that the antiangiogenic
activity of PPAR<italic>γ</italic> can be accomplished either by blocking the production the angiogenic
ELR+CXC chemokines by cancer transformed cells or by inducing expression of the
thrombospondin-1 receptor CD36 in endothelial cells [##REF##15799829##42##–##REF##17548167##44##] In
addition, latest exciting data, which showed that PPAR<italic>γ</italic> agonists were able to inhibit the
canonical WNT signaling in human colonic epithelium, raises hopes that such
agents can possibly block cancer initiation at a stem cell level [##REF##17634527##45##].</p> <p>It must be
underlined herein that despite demonstration of cancer-preventive effects of
PPAR<italic>γ</italic> ligands in vitro, clinical trials and animal
models failed so far to show significant benefits [##REF##16916271##46##]. The fact
that PPAR<italic>γ</italic> ligands have been used in clinic
trials at concentrations above those needed to elicit receptor agonistic activity
poses questions for receptor-independent off-target effects [##REF##17200362##47##].</p> <title>3.1. PPAR<italic>γ</italic> and gastrointestinal cancer</title> <p>PPAR<italic>γ</italic> are heterogeneously expressed throughout the
gastrointestinal epithelium, showing significant differences in abundance,
distribution, and functions. This
protein is principally expressed in differentiated epithelial colonic cells,
preferably in the proximal colon [##REF##10467224##48##]. Sarraf et al. showed that PPAR<italic>γ</italic> activation could stimulate a
program that is characteristic of colonic cell differentiation [##UREF##5##49##].</p> <p>A functional
genomics analysis conducted for the identification of PPAR<italic>γ</italic> gene targets revealed that the
majority of these genes were transcribed throughout the colon, but their
expression varied in cells purified from the proximal colon and in those from
the distal colon. Metabolic functions of PPAR<italic>γ</italic> were elicited primarily in the proximal colon,
whereas signaling functions were recognized in the distal colon. Interestingly,
TZDs transactivated the PPAR<italic>γ</italic> gene targets at the proximal colon but repressed them in the distal
colon. TSC22, a TGF<italic>β</italic> target gene known to inhibit colon cell proliferation, was also
identified as a PPAR<italic>γ</italic> target gene [##REF##12468551##50##]. It is
worth mentioning that both TGF<italic>β</italic> and PPAR<italic>γ</italic> pathways attenuate during transition from adenoma to carcinoma [##REF##16574647##51##]. From a
pharmacological point of view, Yamazaki at al. showed that activation of the RXR/PPAR<italic>γ</italic>
heterodimer by their respective ligands could be considered a useful chemopreventive
strategy for colorectal cancer. They found that a combination of the RXR alpha ligand 9-cis-retinoic acid with ciglitazone synergistically inhibited the cell growth and induced
apoptosis in Caco2 human colon cancer cells that expressed high levels of p-RXR
alpha protein [##REF##17604322##52##].</p> <p>In
the most widely used preclinical model of sporadic colon carcinogenesis, the
azoxymethane-treated mice, activation of PPAR<italic>γ</italic> suppressed carcinogenesis
but only before damage to the APC/beta-catenin pathway [##REF##12370429##53##]. However, two papers
published ten years ago reported that troglitazone and rosiglitazone increased occurrence
of colon tumors in mice-caring mutations in the <italic>APC</italic> gene [##REF##10467224##48##, ##UREF##6##54##]. Moreover, although
pioglitazone was later reported to suppresses colon tumor growth in Apc+/− mice
[##REF##14611672##55##], biallelic knockdown of
PPAR<italic>γ</italic> in
colonic epithelial cells was associated with an increase of tumor incidence [##REF##16858678##56##]. It should be reminded, however, that
although TZDs are considered pure PPAR agonists, they also wield off-target
effects not mediated through linkage to PPAR receptors. An in-depth analysis of the role of TZDs against
colon cancer can be facilitated through development of tissue-specific PPAR<italic>γ</italic> knockout mice [##REF##17978568##57##]. Interestingly, a
small phase II clinical trial using 
troglitazone failed to document tumor responses in patients with advance
stage metastatic colon cancer [##UREF##7##58##].</p> <p>Overall, existing evidence indicates that PPAR<italic>γ</italic> agonists have a potential 
to inhibit cancer formation in the distal colon, but they are practically inactive in advanced 
stages of colon cancer.</p> <title>3.2. PPAR<italic>γ</italic> and lung cancer</title> <p>Lung cancer is a
major global health problem because of its incidence and mortality. It remains
the top cancer killer worldwide to which early-detection strategies and
development of new therapies failed so far to improve its lethal outcome [##REF##17873161##59##]. This
tobacco-related cancer epidemic persists despite public implementation of
tobacco control measures because the majority of tobacco-smoke users declare
powerlessness to quit. Therefore, the search for potent chemopreventive agents
and the development of effective chemoprevention strategies for lung cancer is
a viable pursuit highly justified [##REF##14602246##60##, ##REF##15886305##61##].</p> <p>Several studies
have shown that PPAR<italic>γ</italic> agonists can inhibit growth
and induce changes associated with differentiation and apoptosis in lung cancer
[##REF##10706135##62##–##REF##12391285##64##]. TZDs
induced upregulation of PTEN and p21, downregulation of cyclins D and E, and
reduced expression of fibronectin and its receptor integrin <italic>α</italic>5<italic>β</italic>1 in human lung
carcinoma cell lines [##REF##16386327##65##–##REF##15677767##68##].</p> <p>A first evidence
of clinical efficacy of PPAR<italic>γ</italic> agonists as
cancer chemopreventives in lung cancer was recently published. A retrospective analysis of a database from
ten Veteran Affairs medical centers revealed a significant reduction (33%) in
lung cancer risk in diabetic patients who were treated with TZDs compared with
nonusers of TZDs [##REF##17442990##69##]. However,
other studies damped early this enthusiasm by showing that diabetic patients
treated with TZDs were at increased risk for cardiovascular complications [##REF##17517853##70##].</p> <p>It is critical to understand that cancer-protecting effects of PPAR<italic>γ</italic> agonists in lung cancer can be PPAR<italic>γ</italic> dependent but also PPAR<italic>γ</italic> independent [##REF##17975488##71##]. Characteristically, TZDs suppressed the expression of antiapoptotic
mediator prostaglandin E(2) in NCLC cells through induction of
15-hydroxyprostagladin dehydrogenase [##REF##17412838##72##] and enhanced TRAIL-induced apoptosis through
upregulation of death receptor 5 DR5 and downregulation of c-FLIP in human lung
cancer cells [##REF##17172826##73##].</p> <p>The combination
of PPAR<italic>γ</italic> agonists with other chemopreventive
agents emerges as a challenging issue in lung cancer chemoprophylaxis. Notably,
an amazing synergy of clinically achievable concentrations of lovastatin (an
HMG-CoA reductase inhibitor) and troglitazone was recently shown against lung cancer
cells [##REF##16094629##74##]. This effect
was accompanied by synergistic modulation of E2F-1, p27∧Kip1, CDK2,
cyclin A and RB. In another study, a combination of low-doses of MK886 (5-lipoxygenase
activating protein-directed inhibitor), ciglitazone and 13-cis-retinoic acid,
also demonstrated synergistic inhibitory activity against lung cancer cells [##REF##15899809##75##]. These
studies provide a framework for the development of rationally designed drug
combinations aimed to target simultaneously the PPAR<italic>γ</italic> and other cofactors.</p> <title>3.3. PPAR<italic>γ</italic> and other malignancies</title> <p>Epidemiological studies suggested that high consumption
of carotenoids (known PPAR<italic>γ</italic> activators) could protect women
from the development of breast cancer [##REF##9486468##76##, ##REF##11415946##77##]. These findings are also
supported by experiments which show that activation of PPAR<italic>γ</italic> can induce terminal
differentiation, cell cycle arrest, or apoptosis of preneoplastic and cancerous
mammary epithelial cells [##REF##9660931##78##–##REF##9671760##80##]. Unfortunately, this is not the case for advanced breast
cancer: a phase II trial of troglitazone in patients
with breast cancer metastases failed recently to prove clinical benefits [##REF##12846423##81##].</p> <p>Prostate cancer appears to be an attractive
tumor target for PPAR<italic>γ</italic> agonists because cancerous prostate
cells express higher levels of PPAR<italic>γ</italic> compared with their normal counterparts [##REF##10984506##82##]. Moreover,
it has been shown that PPAR<italic>γ</italic>1/2 activation suppressed the high level of
endogenous COX-2 in normal
prostate epithelial cells [##UREF##8##83##] while TZDs mediated
apoptosis in prostate cancer cells through inhibition of Bcl-xL/Bcl-2 functions
[##REF##15735046##84##]. In the
clinical setting, reduction and prolonged stabilization of prostate-specific antigen
levels were demonstrated
in patients treated with troglitazone [##REF##10984506##82##, ##REF##11034093##85##]. The
above data provide a rationale to consider investigating PPAR<italic>γ</italic> ligands for their role in preventive and possibly therapeutic management
of prostate cancer.</p> <p>In gynecological cancer, Wu et al. reported that rosiglitazone could
block or delay the development of hyperplasia and subsequent endometrial
cancer. This PPAR<italic>γ</italic> agonist induced apoptosis in both PTEN intact
and PTEN null cancer cell lines and decreased proliferation of the endometrial
hyperplastic lesions in a PTEN(+/−)
murine model [##REF##18334011##86##].</p> <p>In human
pancreatic cancer cell lines, treatment with TZDs was found to induce cell
cycle arrest and increase expression of pancreatic differentiation markers [##REF##11078801##87##, ##REF##11034103##88##]. Moreover,
activation of PPAR<italic>γ</italic> together with RXR resulted
in suppression of pancreatic cancer cell growth through suppression of cyclin
D1 [##REF##11895107##89##].</p> <p>Among sarcoma
tumors, it is liposarcomas which are considered targets for PPAR<italic>γ</italic> agonists because they show a high expression of this nuclear receptor [##REF##8990192##90##]. However,
although pioglitazone was found capable to terminally differentiate human
liposarcoma cells in vitro, it failed an early phase II trial despite induced
changes in relevant target genes [##REF##14562008##91##].</p> <p>In thyroid
cancer, a functional chromosomal translocation of part of <italic>PAX</italic>8 gene which encodes the DNA-binding domain to the activation
domain of the PPAR<italic>γ</italic> gene has been
detected in patients with follicular type carcinoma [##REF##10958784##92##]. This chimeric
fusion protein is resistant to PPAR<italic>γ</italic> ligands, invalidating any anticancer effects of PPAR<italic>γ</italic> ligands in this setting. However,
it has been suggested that PPAR<italic>γ</italic> ligands could
have activity in combination with retinoids and/or histone deacetylase
inhibitors in thyroid tumors which express both PPAR<italic>γ</italic> and also RXR<italic>γ</italic> [##REF##16029127##93##, ##REF##15299084##94##].</p> <title>4. PPAR<italic>γ</italic> AS A MEDIATOR TO CANCER PROTECTING
NATURAL PRODUCTS</title> <p>Evidence has
accumulated which affirms that bioactive natural compounds can play an important role in cancer
chemoprevention through modulation of PPAR<italic>γ</italic>. Preclinical studies and
epidemiological data support that tumor growth and metastasis can be restrained
or delayed by several herbal products [##REF##12195161##95##–##REF##17487840##98##].
Moreover, it is believed that novel agents derived from bioactive
phytochemicals can be used as adjuncts to enhance therapeutic efficacy of
standard treatments [##REF##17258704##99##, ##REF##16551868##100##]. Among natural products, triterpenoids,
flavononoids, carotenoids, and linoleic acid are the most extensively studied
as cancer chemopreventives and have invariably been found to operate as PPAR<italic>γ</italic> activators.</p> <p>Terpenoids of
plant origin have shown antitumor activity which indicates a potential role for
these compounds as cancer chemopreventives [##REF##16551868##100##–##REF##17125231##102##]. Specifically,
2-cyano-3,12-dioxooleana-1,9-dien-28-oic
acid (CDDO), a synthetic triterpenoid, which was shown to activate PPAR<italic>γ</italic> and induce
growth arrest and apoptosis in treated
breast cancer cells
[##REF##14522919##103##]; also, glycyrrhizin
the major triterpene gycoside phytochemical in licorice root and the
triterpenoid acid betulinic acid which is found in the bark of several species
of plants, both have shown pro-PPAR<italic>γ</italic> activities in
cancer cells. These phytochemicals were found to induce expression of
proapoptotic protein caveolin-1 and the tumor-suppressor gene Kruppel-like
factor-4 (KLF-4) in colon and pancreatic cancer cells [##REF##17513608##104##, ##REF##17724373##105##]. It
should though be noted that although caveolin-1 is generally considered a proapoptotic
molecule, it has also been associated with drug resistance and possibly metastasis
[##REF##12414512##106##]. It is believed that some PPAR-<italic>γ</italic> agonists
induce whilst others repress caveolin-1 [##REF##12813462##107##].</p> <p>Isoflavones are well
known to function as phytoestrogens. They bind to the estrogen-related
receptors but also to PPAR<italic>α</italic>
and PPAR<italic>γ</italic> [##REF##15936643##108##]. As a
result, their biological effects are determined by the balance between
activated ERs and PPAR<italic>γ</italic> [##REF##12421816##109##]. Liang et al. investigated apigenin, chrysin,
and kaempferol in mouse macrophages and found that these flavonoids stimulated PPAR<italic>γ</italic> transcriptional activities as allosteric effectors rather than pure
agonists [##REF##11343698##110##]. In the
clinical setting, purified isoflavones have only been investigated for safety,
bioavailability, and pharmacokinetics in men with early-stage prostate cancer [##REF##15231450##111##–##UREF##10##114##].</p> <p>Carotenoids are another class of phytochemicals found
to activate PPAR<italic><italic>γ</italic></italic> in cancer cells. Hosokawa
et al. reported that the edible carotenoid fucoxanthin, when combined with
troglitazone, induced apoptosis of Caco-2 cells [##REF##15535974##115##]. Moreover, in epidemiological studies, consumption of carotenoids was shown to protect against breast cancer [##REF##9486468##76##, ##REF##11415946##77##].
Interestingly, Cui et al. unveiled recently the molecular mechanisms which underlie the chemopreventive
activity of <italic>β</italic>-carotene against breast cancer. They found that <italic>β</italic>-carotene
significantly increased PPAR<italic>γ</italic> mRNA and protein levels in
a time-dependent fashion, while 2-chloro-5-nitro-N-phenylbenzamide (GW9662), an
irreversible PPAR<italic>γ</italic> antagonist, attenuated apoptosis caused by <italic>β</italic>-carotene in cancer-transformed cells [##REF##17911009##36##].</p> <p>Linoleic acid, a naturally occurring omega-6
fatty acid which is abundant in many vegetable oils, has been studied
comprehensively for its prophylactic effects against cancer formation [##REF##15316938##116##]. Conjugated linoleic acid, which is found especially in eggs and in the
meat and dairy products of grass-fed ruminants, was shown to modulate cell-cell
adhesion and invasiveness of MCF-7 cells through regulation of PPAR<italic>γ</italic> expression [##REF##17354222##117##]. Moreover
<italic>α</italic>-eleostearic acid (ESA), a linolenic acid isomer, induced apoptosis in
endothelial cells and inhibited angiogenesis, also through activation of PPAR<italic>γ</italic> [##REF##18174233##118##]. More recent studies brought up additional
evidence and provided insights into molecular mechanisms of the protective
effects of linoleic acid against colon cancer. Yasui et al. reported that
9trans-11trans-conjugated linoleic acid inhibited the development of
azoxymethane-induced colonic aberrant crypt foci in rats at preinitiation and
postinitiation level through activation of PPAR<italic>γ</italic> and downregulation of
cyclooxygenase-2 and cyclin D1 [##REF##17927506##119##]. In
addition, Sasaki at al.
showed that linoleic acid was capable to inhibit azoxymethane-induced
transformation of intestinal cells and tumor formation [##REF##16094650##120##]. In most studies,
the differentiation-promoting and carcinogenesis-blocking effects were mostly attributed
to activation of PPAR<italic>γ</italic> by linoleic acid products [##REF##12949056##121##]. Finally,
apart from its direct action as a PPAR<italic>γ</italic> activator, linoleic acid
was found to modulate interactions between PPAR<italic>β</italic>/<italic>δ</italic> and PPAR<italic>γ</italic> isoforms [##REF##16288226##122##].</p> <p>Finally, in the class of capsaicinoids, capsaicin, the
spicy component of hot peppers, was shown to induce apoptosis of melanoma as
well as colon and prostate cancer cells, and was associated with activation of the PPAR<italic>γ</italic> in the case of colon cancer [##REF##15383218##123##–##REF##17306913##125##]. However, controversy exists regarding
cancer-preventing and cancer-promoting effects of capsaicin [##REF##8621114##126##, ##REF##11604990##127##].</p> <p>It must be noted that besides their PPAR<italic>γ</italic>-mediated effects, natural products can also induce
transcription of detoxification enzymes glutathione S-transferases (GST) which are known to protect cells from
chemical-induced carcinogenesis [##REF##9815533##128##, ##REF##11350917##129##]. Recently, Park et al. examined GSTA2 gene
induction by thiazolidinedione and 9-cis-retinoic acid and investigated the
molecular basis of PPAR<italic>γ</italic>/RXR-mediated GSTA2 induction in the
H4IIE hepatocytes. They found that both PPAR<italic>γ</italic> and RXR agonists could increase the expression of GSTA2 but treatment of cells
with a combination of PPAR<italic>γ</italic> and RXR agonists
produced synergistic increase [##REF##15150131##130##]. This data
suggest that cancer-preventive functions of PPAR<italic>γ</italic> activators may be related to some
extent to a parallel induction of GSTA2.</p>
<fig id="fig1" position="float"><label>Figure 1</label><caption><p>
<italic>Peroxisome
proliferator-activated receptor-<italic>γ</italic> and ligands: pathways
and functions.</italic> PPAR<italic>γ</italic> protein exhibits a structural organization
consisting of three functional domains: an N-terminal domain, a DNA-binding
domain (DBD) and a carboxy-terminal ligand binding domain (LBD). PPAR<italic>γ</italic> forms heterodimers with a second member of the
nuclear receptor family, the retinoic X receptor (RXR). Unliganded PPAR<italic>γ</italic> suppresses transcription (pathway A) either by
interfering with key transcription factors (pathway A1) or through recruitment
of corepressors (CoRep) on a PPRE element (pathway A2). Ligand binding to PPAR<italic>γ</italic> (pathway B) triggers conformational changes that lead
to dissociation of corepressors (CoRep) and subsequent association of
coactivators (CoAct). The complex is binding to PPREs and triggers
transcription (pathway B). PPARs ligands can also
exert their action through PPAR<italic>γ</italic>-independent mechanisms
also (pathway C). For instance in NSCLC cell lines activation of TNF-TRAIL
induce apoptosis, while PGE<sub>2</sub> degradation, trough 15-hydroxyprostagladin dehydrogenase induction, results in enhanced epithelial
differentiation. In endothelial cells PPAR<italic>γ</italic>
ligands can markedly boost expression of CD36 which
functions as the receptor of endogenous antiangiogenic molecule
thrombospondin-1, thereby potentiating the apoptotic response. (PFAs: polyunsaturated
fatty acids, TZDs: thiazolidinediones, PPRE: peroxisome proliferator response
element, TNF: tumor necrosis factor, TRAIL: TNF-related apoptosis-inducing
ligand, NSCLC: non-small cell lung carcinoma).</p></caption></fig>
<graphic xlink:href="PPAR2008-436489.001"/>
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PPAR Res. 2008 Sep 3; 2008:436489