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The role of PPARs in cancer

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. PPARalpha is mainly expressed in the liver, where it activates fatty acid catabolism. PPARalpha activators have been used to treat dyslipidemia, causing a reduction in plasma triglyceride and elevation of high-density lipoprotein cholesterol. PPARdelta is expressed ubiquitously and is implicated in fatty acid oxidation and keratinocyte differentiation. PPARdelta activators have been proposed for the treatment of metabolic disease. PPARgamma2 is expressed exclusively in adipose tissue and plays a pivotal role in adipocyte differentiation. PPARgamma is involved in glucose metabolism through the improvement of insulin sensitivity and represents a potential therapeutic target of type 2 diabetes. Thus PPARs are molecular targets for the development of drugs treating metabolic syndrome. However, PPARs also play a role in the regulation of cancer cell growth. Here, we review the function of PPARs in tumor growth.
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Hindawi Publishing Corporation
PPAR Research
Volume 2008, Article ID 102737, 15 pages
doi:10.1155/2008/102737
Review Article
The Role of PPARs in Cancer
Keisuke Tachibana,1Daisuke Yamasaki,1, 2 Kenji Ishimoto,1, 3 and Takefumi Doi1, 2, 3
1Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
2The Center for Advanced Medical Engineering and Informatics, Osaka University, 2-2 Yamadaoka, Suita,
Osaka 565-0871, Japan
3Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Correspondence should be addressed to Keisuke Tachibana, nya@phs.osaka-u.ac.jp
Received 1 April 2008; Accepted 20 May 2008
Recommended by Dipak Panigrahy
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone
receptor superfamily. PPARαis mainly expressed in the liver, where it activates fatty acid catabolism. PPARαactivators have been
used to treat dyslipidemia, causing a reduction in plasma triglyceride and elevation of high-density lipoprotein cholesterol. PPARδ
is expressed ubiquitously and is implicated in fatty acid oxidation and keratinocyte dierentiation. PPARδactivators have been
proposed for the treatment of metabolic disease. PPARγ2 is expressed exclusively in adipose tissue and plays a pivotal role in
adipocyte dierentiation. PPARγis involved in glucose metabolism through the improvement of insulin sensitivity and represents
a potential therapeutic target of type 2 diabetes. Thus PPARs are molecular targets for the development of drugs treating metabolic
syndrome. However, PPARs also play a role in the regulation of cancer cell growth. Here, we review the function of PPARs in tumor
growth.
Copyright © 2008 Keisuke Tachibana et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
1. INTRODUCTION
Peroxisome proliferator-activated receptors (PPARs) are li-
gand-activated transcription factors that belong to the nu-
clear hormone receptor superfamily [1]. PPARs bind to a
direct repeat of two hexanucleotides, spaced by one or two
nucleotides (the DR1 or DR2 motif) as heterodimers with
the retinoid X receptor (RXR), and activate several target
genes [24]. These peroxisome proliferator responsive ele-
ments (PPREs) are found in various genes that are involved
in lipid metabolism and energy homeostasis, including lipid
storage or catabolism, and fatty acid transport, uptake, and
intracellular binding [5]. Three subtypes, PPARα,PPARδ
(also known as PPARβ), and PPARγ, have been identified
and these subtypes with a high degree of sequence con-
servation of each subtype across various species have been
characterized. The DNA-binding domains of the three sub-
types are 80% identical, while their ligand-binding domains
exhibit a lower degree (approximately 65%) of identity
(Figure 1). Consistent with this relatively high divergence
among the subtype-specific ligand-binding domains, dier-
ential activation of PPARs by endogenous and exogenous
compounds may account for the specific biological activity
of the three PPAR subtypes [6,7].
PPARαis expressed in the liver, kidney, small intestine,
heart, and muscle, where it activates fatty acid catabolism
and is involved in the control of lipoprotein assembly [8].
PPARαis activated by several molecules, such as long chain
unsaturated fatty acids, eicosanoids, and hypolipidemic dr-
ugs (e.g., fenofibrate) [912]. PPARαactivators have been
used to treat dyslipidemia, causing a reduction in plasma
triglyceride and elevation of high-density lipoprotein (HDL)
cholesterol [13,14]. PPARδis expressed ubiquitously and is
implicated in fatty acid oxidation, keratinocyte dierentia-
tion, wound healing, and the response of macrophages for
very low-density lipoprotein [1519]. PPARδactivators have
been proposed for the treatment of metabolic disease and are
under clinical trial [20,21]. There are two PPARγisoforms:
PPARγ1andγ2[22,23]. PPARγ2,whichisgeneratedby
alternative splicing, contains an additional 28 amino acids at
the N-terminal compared to PPARγ1. PPARγ3 is a splicing
variant of PPARγ1 and gives rise to the same protein [24].
2PPAR Research
hPPARα
hPPARδ
hPPARγ
γ2
γ1
1
1
1 100 167 244 468 (a.a.)
DBD LBD
1 72 139 216 441 (a.a.)
85% 70%
137 204 280 505 (a.a.)
109 176 252 477 (a.a.)
84% 64%
A/B C D E/F
(a)
Corepressor
complex
PPAR RXR
Target g e n e
PPRE
Repression
5’-AGGTCA-(n)1–2-AGGTCA-3’
Ligand
Coactivator
complex
PPAR RXR RNA Pol II
Activation
Target g e n e
PPRE
(b)
Figure 1: The general features of human PPARs. (a) Structure and functional domain of human PPARs. A/B, C, D, and E/F indicate N-
terminal A/B domain containing a ligand-independent activation function 1, DNA-binding domain (DBD), hinge region, and C-terminal
ligand-binding domain (LBD), respectively. The number inside each domain corresponds to the percentage of amino acid sequence identity
of human PPARδand PPARγrelative to PPARα. (b) PPAR/RXR heterodimers bind to a PPRE located in the promoter of target genes through
the DBD. Unliganded PPAR associates with the corepressor complex. In the presence of ligand, the ligand-bound LBD associates with the
coactivator complex.
PPARγ2 is expressed exclusively in adipose tissue and plays a
pivotal role in adipocyte dierentiation, lipid storage in the
white adipose tissue, and energy dissipation in the brown
adipose tissue [22,25]. On the other hand, PPARγ1isex-
pressed in the colon, the immune system (e.g., monocytes
and macrophages), and others. Except for the function
of PPARγ2 in adipose tissue, PPARγalso participates in
inflammation, cell cycle regulation, and other functions
[26]. PPARγis involved in glucose metabolism through the
improvement of insulin sensitivity and represents a potential
therapeutic target of type 2 diabetes [26]. Indeed, insulin-
sensitizing thiazolidinedione (TZD) drugs are PPARγligands
[27]. Thus PPARs are molecular targets for the development
of drugs to treat type 2 diabetes and metabolic syndrome.
On the other hand, PPARs also play a role in the regulation
of cancer cell growth.
2. PPARαAND CANCER
Fibrates, which are relatively weak PPARαligands, are useful
for the treatment of dyslipidemia [7,911]. Fibrates lower
serum triglyceride levels and increase HDL levels through
the activation of PPARα[5]. PPARαinduces lipoprotein
lipase (LPL) expression, reduces the expression levels of
apolipoprotein C-III (ApoC-III), a natural LPL inhibitor,
and stimulates the uptake of cellular fatty acids and the
conversion of fatty acids to acyl-CoA derivatives [5,28,29].
These catabolism functions are mediated by upregulating
the expression of a series of genes-related carbohydrate and
lipid metabolism [5,30]. In addition, PPARαincreases the
expressions of ApoA-I and ApoA-II, resulting in raising HDL
cholesterollevelsinhumans[31,32]. Thus PPARαplays
a central role in the control of fatty acid and lipoprotein
metabolism, and improves plasma lipid profiles. Although
peroxisome proliferators have carcinogenic consequences in
the liver of rodents, epidemiological studies suggest that
similar eects are unlikely to occur in humans [10,3336].
Several mechanisms have been proposed to explain the
carcinogenesis of peroxisome proliferators in rodents. Peters
et al. reported that wild-type mice treated with the Wy-
14,643 showed increase of replicative DNA synthesis in hep-
atic cells and developing liver tumors with 100% incidence,
whereas PPARα-nullmicewererefractorytothiseect [37].
Peroxisome proliferators increase the peroxisome volume
and number and result in an increase in hydrogen peroxide
(H2O2)levels[3840]. These eects may be mediated in
part by the increased expression of peroxisomal enzymes that
produce H2O2,suchasacylCoAoxidase(ACO)[3941].
PPARαupregulates the expression levels of ACO via PPRE
in the promoter region [42,43]. A stably transfected African
Keisuke Tachibana et al. 3
green monkey kidney cells (CV-1) overexpressing rat ACO
increased H2O2production, formed transformed foci, and
grew eciently in soft agar when the cells were treated
with linoleic acid [44]. Furthermore, when these cells were
transplanted into nude mice, these cells formed solid tumors
[44]. An increase of intracellular levels of H2O2couldleadto
DNA damage via a variety of mechanisms [45]. Any reduced
iron present can catalyze the cleavage of H2O2, via the Fenton
reaction, to produce hydroxyl radicals (HO)[46]. The
HOattacks guanine residues, producing residues of 8-oxo-
7,8-dihydroguanine (8-oxoguanine). When DNA synthesis
occurs before the 8-oxoguanine is repaired, this damaged
base will have a chance to pair with adenine nucleotide, re-
sulting in a mutation in the daughter cells [47]. In addition,
antioxidants inhibit ciprofibrate-induced hepatic tumorige-
nesis by scavenging active oxygen [48]. Thus oxidative stress
by peroxisome proliferators acts as a driving force to malig-
nancy. The activation of PPARαalso leads to increased hepa-
tocellular proliferation and inhibition of apoptosis. Chron-
ic administration of nafenopin, PPARαagonist, to mice
causes significant increase in the liver weight, hepatic DNA
synthesis, and the development of hepatocellular carcinomas
[49]. Nafenopin treatment of primary cultures of adult rat
hepatocytes also stimulated DNA synthesis [50]. Indeed,
Peters et al. showed that mRNAs encoding cyclin-dependent
kinase (CDK) 1, CDK4, cyclin D1, and c-myc and their pro-
teins, which induce cell proliferation, increased in wild-type
mice fed by Wy-14,643 but not in PPARα-nullmice[51].
Increase of the average liver weight and the levels of mRNAs
encoding cell cycle regulation, such as CDK4, proliferating
cell nuclear antigen (PCNA) and cyclin B1, were also found
in wild-type mice fed by bezafibrate, the less specific PPARα
agonist, and these eects were not found in PPARα-null
mice [52]. Moreover, the treatment of the primary culture
of rat hepatocytes and the rat hepatoma cell line, FaO, with
nafenopin suppressed apoptosis [53,54]. Thus the activation
of PPARαleads to the increase of oxidative stress, induction
of cell proliferation and inhibition of apoptosis, indicating
that PPARαincreases hepatocarcinogenesis in mice.
A number of experimental observations suggest that
there is a species dierence between rodents and humans in
the response to PPARαagonists, although the functional
dierences of PPARαderived from species are not clear
(Tabl e 1). One possible explanation for the dierence is the
expression levels of PPARαin the liver. The expression levels
of PPARαin human liver are approximately one order less
than that observed in mouse liver [55]. Small expression
levels of PPARαcould allow PPREs to be occupied by other
members of the nuclear receptor superfamily, such as RXR,
the chicken ovalbumin upstream promoter transcription fac-
tor I (COUP-TFI), COUP-TFII, hepatocyte nuclear factor-4
(HNF4), retinoic acid receptor (RAR), and thyroid hormone
receptor (TR), and aect responsiveness to peroxisome pro-
liferators [5662]. We and others have shown that elevated
expression of PPARαin HepG2 cells dramatically increased
the expression of several target genes, such as 3-hydroxy-3-
methylglutaryl-CoA synthase 2 (mitochondrial) (HMGCS2),
carnitine palmitoyltransferase 1A (CPT1A), and long chain
fatty acyl-CoA synthetase (ACS) [30,63,64]. In this way,
Tab l e 1: Summary of the species dierences of PPARα.
Human Rodent
PPARαexpression levels + ++
PPARαvariants Yes ?
Peroxisome proliferation +/+
Fatty acid metabolism + +
Expression of cell cycle regulator genes +/+
Expression of miRNA (let-7C) +
Hepatocellular proliferation +/+
Apoptosis +
Liver tumor +/++
the lower expression levels of PPARαin human liver might
contribute to holding down peroxisome proliferation and
subsequent pathologic eects. Another explanation is that
several PPARαvariants, which lack the entire exon 6 or
contain mutations, are detected in human cells and these
variants act as a dominant negative regulator of PPAR-
mediated gene transcription [55,65,66]. But this has not
been found in rodents yet. One PPARαvariant containing the
mutation prevents the suppression of hepatocyte apoptosis
by nafenopin [55,65,66]. Thus the expression levels of
PPARαvariants might aect the response to peroxisome
proliferators. Next, there appears to be sequence dierences
in the PPRE found in the promoter region of ACO. Osumi
et al. identified ACO to be a direct PPARαtarget gene and
a functional PPRE located in the proximal promoter of the
rat ACO gene [42]. In contrast to the rodent ACO gene
promoter, the human ACO gene promoter diersatthree
bases within the PPRE from the rat ACO promoter and
appears refractory to PPARα[42,67,68]. This human PPRE
was unable to drive peroxisome proliferators-induced gene
transcription in cell-based assays [6769]. Indeed, human
liver cell lines and primary hepatocytes did not induce
ACO mRNA by treatment with fibrates or other PPARα
agonists [63,64]. A similar pattern, such dierences between
human and other species, was observed in the expression
of ApoA-I gene [31]. Fibrates influence the ApoA-I gene
expression, raising it in humans, and lowering it in rodents.
These dierences are due to a combination of two distinct
mechanisms implicating the nuclear receptors PPARαand
Rev-erbα, a negative regulator of gene transcription [31].
The species-distinct regulation is due to sequence dierences
in cis-acting elements in their respective promoters leading
to repression by Rev-erbαof rat ApoA-I and activation by
PPARαof human ApoA-I. There is a positive PPRE in the
human ApoA-I promoter but not in rats. The expression of
Rev-erbαis induced by fibrates [3,31]. In the case of rat,
this induction leads to the repression of the ApoA-I gene
expression through an Rev-erbαresponse element. On the
other hand, there is no Rev-erbαresponse element in the
humanApoA-Igene[31]. Thus the sequence dierences
in cis-acting elements cause the species-distinct regulation
of target genes expression by peroxisome proliferators.
However, the mechanism of the species dierences is not
known in detail.
4PPAR Research
To determine the mechanism of species dierence in
response to peroxisome proliferators, Gonzalez et al. gen-
erated a liver-specific PPARαhumanized mouse line
(hPPARαTetO mice) in which the human PPARαwas expr-
essed in the liver in a PPARα-null background under the
control of the tetracycline (Tet) responsive regulatory system
[7072]. The expression of several target genes encoding
peroxisomal and mitochondrial fatty acid metabolizing
enzymes were elevated in hPPARαTet O mice fed Wy-14,643
or fenofibrate, resulting in the decrease of serum triglycerides
[70,73]. However, the expressions of various genes involved
in cell cycle regulation (PCNA, c-myc, CDK1, CDK4, and
cyclins) in the liver were unaected by Wy-14,643. In ad-
dition, hPPARαTetO mice were resistant to Wy-14,643-
induced hepatocarcinogenesis [70,73]. Recently, Shah et al.
showed that Wy-14,643 regulated mice hepatic MicroRNA
(miRNA) expression via a PPARα-dependent pathway [74].
miRNAs are a class of nonprotein-coding, endogenous, small
RNAs, and regulate gene expression by translational repres-
sion and mRNA cleavage [75]. Some miRNAs regulate cell
proliferation and apoptosis processes that are important in
cancer formation [76]. The activation of PPARαwith Wy-
14,643 inhibits the expression of miRNA let-7C, which func-
tions as a tumor suppressor gene [74]. let-7C degrades c-myc
mRNA by binding to 3’ untranslated region (UTR) of the c-
myc gene. Treatment of mice with Wy-14,643 showed that
let-7C expression was decreased and a subsequent increase
in c-myc was observed. Following an increase in c-myc,
the levels of the oncogenic mir-17 miRNA cluster were
increased [74]. In this way, inhibition of the let-7C signaling
cascade may lead to increased hepatocellular proliferation
and tumorigenesis. In contrast, hPPARαTet O mice do not
exhibit downregulation of let-7C and induced c-myc and
mir-17 expression [74]. Furthermore, Yang et al. generated
another type of PPARαhumanized mice, hPPARαPAC mice,
that has the complete human PPARαgene sequence includ-
ing 5’ and 3’ flanking sequences on a P1 phage artificial
chromosome (PAC) genomic clone, introduced onto the
mouse PPARα-null background [71]. Upon treatment with
the peroxisome proliferators (Wy-14,643 or fenofibrate),
hPPARαPAC mice exhibited peroxisome proliferation, lower-
ing of serum triglycerides, and induction of PPARαtarget
genes encoding enzymes involved in fatty acid metabolism.
However, let-7C expression was not decreased and the
expression levels of c-myc, cyclin D1 and CDK4 were not
increased [71]. Thus these observations suggest that the
species dierences in response to peroxisome proliferators
could be due in part to a dierential ability of the mouse
and human PPARαto suppress let-7C gene expression [74].
However, the mechanism involved in PPARα-dependent
repression of let-7C is unclear. The dierences between the
wild-type mice and PPARαhumanized mice could be caused
by the structural dierences between human and mouse
PPARαand dierential coactivator recruitment. However,
additional investigation is required to better understand
and clarify the mechanism of action of PPARαin causing
hepatocarcinogenesis.
3. PPARδAND CANCER
TheroleofPPARδin oncogenesis is controversial, especially
in colon cancer. Some reports show that PPARδpromotes
tumorigenesis by increasing cell proliferation. Indeed, the
levels of PPARδmRNA are increased in both human and
rodent colorectal carcinomas [77,78]. PPARδis a potential
downstream target gene of the adenomatous polyposis coli
(APC)/β-catenin/T cell factor-4 (TCF-4) pathway [77]. APC
is a tumor suppressor gene and is mutated in familial
adenomatous polyposis (FAP) and most sporadic colorectal
tumors [7983]. β-catenin, which binds to APC and axin in
a large protein complex, can be phosphorylated by glycogen
synthase kinase-3β(GSK3β) and is followed by ubiquiti-
nation and degradation. Mutation of APC results in the
accumulation of β-catenin, which in turn translocates to the
nucleus and associates with the transcription factor TCF-4
[84]. The β-catenin-TCF-4 transcription complex increases
the transcription of growth-promoting genes, such as c-myc
andcyclinD1[85,86]. The β-catenin-TCF-4 transcription
complex also activates the human PPARδpromoter activity
via TCF-4 binding sites, namely, APC suppresses the PPARδ
expression through the degradation of β-catenin [77]. K-Ras
mutation is found in colorectal cancer [80,87]. Activation
mutations in Ras result in the activation of the mitogen-
activated protein kinase (MAPK) pathway and induce tumor
growth and progression [88]. The expression levels and
activity of PPARδwere increased by the induction of mutated
K-Ras in conditionally K-Ras-transformed rat intestinal
epithelial cells [89]. Thus PPARδis also a downstream target
gene of Ras/Raf/MAPK and extracellular signal-regulated
kinase (ERK) kinase (MEK)/ERK pathway [89]. In this way,
PPARδmay play a role in colon cancer.
Epidemiological studies have shown that nonsteroidal
anti-inflammatory drugs (NSAIDs), such as aspirin, indo-
methacin, and sulindac, reduce the overall number and
size of adenomas in patients with FAP. Healthy individuals
using NSAIDs regularly can lead to a 40–50% reduction in
the relative risk of developing colon cancer [90]. NSAIDs
inhibit cyclooxygenase (COX) activity and thereby reduce
prostaglandin synthesis [91]. COX is a key enzyme in ara-
chidonic acid metabolism and prostaglandin production.
COX catalyzes a two-step reaction that converts arachidonic
acid to prostaglandin H2(PGH2), which in turn serves as
the precursor for the synthesis of all biologically active
prostaglandins, including PGD2,PGE
2,PGF
2α, prostacyclin
(PGI2), and thromboxane A2(TXA2)[92]. COX exists in
two isoforms that are encoded by two separate genes. COX-1
is constitutively expressed in most tissues, on the other
hand, the expression of COX-2 is normally low or absent in
most tissues but is rapidly upregulated by proinflammatory
cytokines [93]. Expression of COX-2 is also elevated in col-
orectal cancer and in a subset of adenomas [94]. Moreover,
since both the introduction of the knockout mutation of
the COX-2 gene into ApcΔ716 mice, a model of human
FAP, and treating ApcΔ716 mice with NSAIDs reduce the
development of intestinal tumors, COX-2 inhibitors have
been considered as therapeutic agents for colorectal poly-
posis and cancer [95]. He et al. reported that NSAIDs
Keisuke Tachibana et al. 5
inhibited the transcriptional activity of PPARδby disruption
of the DNA binding ability of PPARδ/RXR heterodimers,
and ectopic expression of PPARδin the human colorectal
cancer cell line, HCT116, protected the cells from sulindac-
induced apoptosis [77]. PPARδand COX-2 mRNA are
expressed in similar regions in human colon cancer, and
the stable PGI2analog, carbaprostacyclin (cPGI), acts as a
PPARδligand [11,78]. Indeed, ectopic expression of COX-
2 and PGI synthase (PGIS) in the human osteosarcoma
cell line, U2OS, produced high levels of endogenous PGI2
and transactivation of PPARδ[78]. PGE2levels are also
elevated in human colorectal cancers and adenomas, and
PGE2increases the growth and motility of colorectal car-
cinoma cells [96,97]. D. Wang et al. showed that PGE2
promoted resistance to serum starvation-induced apoptosis
of cultured human colon carcinoma cells, LS-174T, through
indirectly upregulation PPARδtranscriptional activity via
a phosphotidylinositol-3-kinase (PI3K)-Akt pathway [98].
Furthermore, PGE2accelerates intestinal adenoma growth of
Apcmin mice, a model of human FAP that harbors a mutation
in the apc gene, via PPARδ[98]. Xu et al. showed that PGE2
activated cytosolic phospholipase A2α(cPLA2α) through
PI3K or MAPK pathway, and subsequently cPLA2αenhanced
PPARδactivity in the human cholangiocarcinoma cells [99].
They also showed that PPARδenhanced COX2 expression
and PGE2production. This positive feedback loop may
play an important role in cholangiocarcinoma cell growth,
although it is not known whether this kind of positive
feedback loop exists in the colorectal cancer cells [99]. Thus
PPARδinduces the cell proliferation through the inhibition
of apoptosis. However, sulindac sulfide induces apoptosis not
only in wild-type HCT116, but also in HCT116 PPARδ-null
cell lines [100]. On the basis of these observations, although
NSAIDs may reduce tumorigenesis through the inhibition of
PPARδactivity, PPARδis not a major mediator of sulindac-
mediated apoptosis.
Recent evidence supports the hypothesis that PPARδ
promotes tumor progression. HCT116 PPARδ-null cell lines
grew slightly more slowly than wild-type HCT116 cells, and
exhibited a decreased ability to form tumors compared with
wild-type mice when inoculated as xenografts in nude mice
[100]. Gupta et al. showed that exposure of Apcmin mice
to 10 mg/kg of GW501516, a high-anity PPARδ-selective
agonist, led to a two-fold increase in polyp number in
the small intestine [101]. The most prominent eect was
on polyp size, mice treated with the PPARδactivator had
a five-fold increase in the number of polyps larger than
2 mm, suggesting that PPARδactivation primarily a-
ected the rate of polyp growth rather than initiating
polyp formation. Pretreatment of wild-type HCT116 cells
with GW501516 significantly suppressed serum starvation-
induced apoptosis in a dose-dependent manner, but not
HCT116 PPARδ-null cells [101]. Furthermore, D. Wang et
al. showed that PPARd//Apcmin mice decreased intesti-
nal adenoma growth and inhibited the tumor-promoting
eect of GW501516 [102]. They also showed that PPARδ
activation with GW501516 upregulated vascular endothelial
growth factor (VEGF) transcription, expression, and peptide
release in intestinal epithelial tumor cells, and subsequently
activated PI3K-Akt signaling [102]. Similar results were
obtained in the human endothelial cells [103,104]. Piqueras
et al. showed that GW501516 induced VEGF mRNA and
peptide release, and thus PPARδinduced endothelial cell
proliferation and angiogenesis [103]. Stephen et al. showed
that the activation of PPARδresulted in increased expression
of VEGF and its receptor fms-related tyrosine kinase 1
(FLT-1), and they suggested that PPARδmight initiate an
autocrine loop for cellular proliferation and possibly angio-
genesis [104]. These results demonstrate that VEGF mediates
the antiapoptotic eects of PPARδin intestinal epithelial
tumor cells by activating the PI3K-Akt cell survival pathway,
and the VEGF autocrine loop plays an important role
in cell survival. Diminished apoptosis is also linked to
downregulated 15-lipoxygenase-1 (15-LOX-1) expression in
colorectal cancer cells. 13-S-hydroxyoctadecadienoic acid
(13-S-HODE), which is the primary product of 15-LOX-1
metabolism of linoleic acid, inhibits cell proliferation and
induces cell cycle arrest and apoptosis in transformed colonic
epithelial cells [105]. 15-LOX-1 protein expression and 13-
S-HODE intracellular levels are decreased in human colonic
tumors [105]. Shureiqi et al. showed that 13-S-HODE bound
to PPARδand then downregulated PPARδexpression and
activation in colorectal cancer cells, DLD-1 and RKO, and
that the loss of PPARδexpression in HCT116 markedly
suppressed 13-S-HODE-mediated apoptosis [106]. 15-LOX-
1 expression also downregulated PPARδexpression and
transcriptional activity in these colorectal cancer cells [106].
Furthermore, NSAIDs increase 15-LOX-1 protein expression
and its product 13-S-HODE levels and downregulate PPARδ
expression in association with subsequent growth inhibition
and apoptosis [106,107]. Thus it is considered possible that
PPARδpromotes the growth of colon cancers.
On the contrary, other reports suggest that ligand acti-
vation of PPARδpromotes the induction of terminal dier-
entiation and inhibition of cell growth. PPARδwas found
in intestinal epithelial cells in both the normal intestine
and adenomas of Apcmin mice [101]. Reed et al. reported
that targeted deletion of the APC alleles in mouse intestines
decreased the expression levels of PPARδmRNA and protein,
although β-catenin and c-myc were increased [108]. Marin
et al. showed that PPARδexpression was reduced in both
the Apcmin mouse colon polyps and azoxymethane (AOM)-
treated wild-type mouse polyps, though the expression lev-
els of PPARδmRNA in colonic epithelium were not dif-
ferent between Apcmin mice and wild-type mice with or
without AOM-treatment [109]. Several reports identified
that the transcription factor binding sites for AP-1,
CCAAT/enhancer-binding proteins, vitamin D receptor, and
others were found in human or mouse PPARδpromoter,
and these transcription factors regulated PPARδexpression
[16,110,111]. However, further investigation is required to
certify the regulation of PPARδexpression in cancer.
Hollingshead et al. reported that GW501516 and
GW0742, highly specific PPARδligands, did not increase the
growth of human colon cancer cell lines (HT-29, HCT116,
and LS-174T) and liver cancer cell lines (HepG2 and HuH7)
cultured in the presence or absence of serum [112]. In
6PPAR Research
addition, treatment of these cell lines with either GW501516
or GW0742 did not change the phosphorylation of Akt,
and no increase in the expression levels of COX2 or VEGF
were detected [112]. Similar results were observed in the
colon or liver of Apcmin mice treated with GW501516 or
GW0742 [109,112]. Barak et al. showed that the average
number of intestinal polyps was not significantly dif-
ferent between PPARd+/+/Apcmin,PPARd+//Apcmin,and
PPARd//Apcmin mice, although this study was limited to
a small number [113]. On the other hand, several studies
showed that colon polyp formation was enhanced in the
absence of PPARδexpression in both PPARd//Apcmin and
AOM-treated PPARd/mice [108,109,114]. Moreover,
Marin et al. showed that the administration of GW0742
had no eect on colon or small intestinal tumorigenesis
in either PPARd//Apcmin or PPARd+/+/Apcmin mice as
compared with controls [109]. In addition, decrease of
colon polyp multiplicity was observed in PPARd+/+AOM-
treated mice administrated with GW0742 compared with
control wild-type mice. This eect was likely due in part
to PPARδ-dependent induction of colonocyte dierentia-
tion and enhancement of apoptosis [109]. Indeed, PPARδ
induces keratinocyte terminal dierentiation, which nor-
mally opposes cell proliferation [115,116]. Hatae et al.
also showed that intracellular PGI2,anendogenousPPARδ
ligand, formed by expressing PGIS in human embryonic
kidney 293 (HEK293) cells, promoted apoptosis by activating
PPARδ[117]. In this way, PPARδinhibits tumor growth by
inducing apoptosis or dierentiation.
Thus the conflicting reports in the literature suggest that
PPARδeither potentiates or attenuates colon cancer. Similar
discrepancies were observed in other tissues. Di-Po¨
ıetal.
showed that the activation of PPARδinhibited apoptosis in
keratinocyte [118]. The activation of PPARδby L-165041,
onetypeofPPARδligand, upregulates 3-phosphoinositide-
dependent kinase-1 (PDK1) and integrin-linked kinase
(ILK) gene expression via PPRE and downregulates phos-
phatase and tensin homolog (PTEN) protein expression,
and subsequently leads to the activation of Akt1 in a PI3K-
dependent manner in mouse primary keratinocytes and
human keratinocyte HaCaT cells [118]. Yin et al. showed
that PPARδligand GW501516 accelerated progestin- and
carcinogen-induced mouse mammary carcinogenesis [119].
Stephen et al. reported that PPARδselective agonists stimu-
lated the proliferation of human breast and prostate cancer
cell lines and primary endothelial cells [104]. On the other
hand, Burdick et al. reported that ligand activation of
PPARδwith GW0742 inhibited the cell growth of either
human keratinocyte cell line N/TERT1 or mouse primary
keratinocytes [120]. In these cells, ligand activation of PPARδ
by GW0742 did not alter expression and/or modulation
of the PTEN/PDK1/ILK1/Akt pathway [120]. Girroir et al.
reported that both GW0742 and GW501516 inhibited the
growth of the human breast cancer cell line, MCF7, and
human melanoma cell line, UACC903 [121].
To date, however, the reason for the contradiction in
these observations is unclear. One explanation for these
conflicting results may be the ability of PPARδto repress the
transcription of target genes. We and others observed that
unliganded PPARδrepressed target gene expression, though
ligand-activated PPARδinduced these genes [30,122124].
It has been reported that unliganded PPARδbound to PPRE
and recruited corepressors, such as B-cell lymphoma 6 (BCL-
6), silencing mediator for retinoid and thyroid hormone
receptor (SMRT), nuclear receptor corepressor (NCoR), and
others. On the other hand, liganded PPARδis thought to
release the corepressor and form a complex with coactivators
[122124]. Furthermore, binding of ligand to the PPARδ
or deletion of PPARδexpression may lead to the release
of BCL-6. Subsequently, BCL-6 represses the transcription
of a number of inflammatory cytokine genes [124]. Thus
the PPARδactivity may be influenced by the cellular envi-
ronment, such as the existence of PPARδligands, cofactors,
and others. From this viewpoint, the conflicting results may
be due to dierences in the condition of cell cultures or
the genetic background of animal models. Secondly, pros-
taglandins, some of which act as PPAR ligands, have a
variety of biological activities. Prostaglandins, synthesized
via the COX pathway from arachidonic acid, are released
outside the cells and lead to changes in the cellular levels of
cyclic AMP and Ca2+ through binding to G-protein-coupled
receptors on the plasma membrane [90]. Indeed, Hatae et
al. suggested that cAMP produced by the PGI2-PGI receptor
(IP)-cAMP pathway might protect vascular endothelial cells
from intracellular PGI2-PPARδ-mediated apoptosis [117].
On the other hand, Fauti et al. showed that the ectopic
expression of COX-2 and PGIS in HEK293 cells results in
a dramatic induction of PGI2synthesis, but no increase in
PPARδtranscriptional activity is observed [125]. Thus they
suggest that PGI2lacks agonistic activity for PPARδ. Since
PGI2is unstable and rapidly hydrolyzed to 6-keto-PGF1α
within minutes and increases the production of intracellular
cAMP via stimulation of adenylyl cyclase through the cell
surface IP receptor, further investigation is necessary to
certify the mechanism of the eect of the PGI2on PPARδ
activity in detail. Therefore, additional analyses are necessary
to define the PPARδfunctions in cancer (Figure 2).
4. PPARγAND CANCER
Cancer cells represent dysregulaton of the cell cycle and lead
to cell proliferation. In this viewpoint, modulators of the cell
cycle and/or apoptosis are useful as chemotherapeutic agents
for cancer [126,127]. A number of investigators have shown
that PPARγwas expressed in a variety of tumor cells, and
the activation of PPARγby ligands led to either inhibition
of cell proliferation or induction of apoptosis (Tab l e 2)
[128,129]. PPARγis expressed in colonic tumors, normal
colonic mucosa, and colon cancer cell lines [130135].
Kitamura et al. showed that TZDs, such as troglitazone and
rosiglitazone, inhibited the cell growth and induced G1 cell
cycle arrest of rat intestinal epithelial cells [136]. The cell
growth inhibition by TZDs was caused by the decrease of
the expression of cyclin D1, critical for entering the S phase
of the cell cycle. TZDs suppressed the cyclin D1 promoter
activity through inhibition of the transcriptional activities of
AP-1 and Ets [136]. Shao et al. demonstrated that treatment
Keisuke Tachibana et al. 7
Tumor progression
Induction of the cell proliferation
Inhibition of apoptosis
Up-regulation of VEGF expression
Enhancement of COX-2 expression
and PGE2production
Tumor suppression
Induction of the terminal
dierentiation
Induction of apoptosis
Inhibition of the cell growth
Figure 2: Does PPARδprogress or suppress tumor growth?
Tab l e 2: The expression of PPARγin cancer.
References
Colonic tumor [135]
Breast tumor [137]
Esophageal tumor [138]
Gastric cancer [139]
Pancreatic cancer [140]
Hepatocellular carcinoma [141]
Adrenocortical carcinoma [142]
Lung tumor [143]
Prostate cancer [144]
Liposarcoma [145]
Thyroid carcinoma [146]
Bladder cancer [147]
Renal cell carcinoma [148]
Melanoma [149]
Squamous cell carcinoma [150]
Cervical carcinoma [151]
Testicular cancer [152]
Neuroblastoma [153]
Pituitary tumor [154]
with rosiglitazone inhibited the K-Ras-induced elevation
of the expression levels of cyclin D1 by inhibition of the
K-Ras-induced phosphorylation of Akt, resulting in the G1
cell cycle arrest [89]. Furthermore, J.-A. Kim et al. showed
that treatment of the human colorectal cell line, HCT15,
with troglitazone induced the expression of p21Cip1/Waf1, that
is, a CDK inhibitor (CKI) and negatively regulates the cell
cycle progression, through the ERK pathway, and inhibited
HCT15 cell growth [155]. PPARγligands also induce apop-
tosis in human colon cancer cells [156]. Chen et al. sho-
wed that PPARγligands, 15-Deoxy-Δ12,14-prostaglandin
J2(15dPGJ2), or ciglitazone, induced apoptosis in HT-29 by
inhibiting nuclear factor kappa B (NF-κB) activity, which
upregulates various antiapoptotic genes, and suppressing the
expression of BCL-2, which protects cells against apoptosis
[133]. Furthermore, using the in vivo mouse model, the
administration of TZD to mice reduced AOM and/or dextran
sodium sulfate-induced formation of aberrant crypts foci
and colon carcinogenesis [131,157]. In addition, PPARγlig-
ands also inhibit the cell growth of several breast cancer cell
lines and mammary gland tumor development [137,158
162]. Elstner et al. showed that PPARγligands, troglitazone,
15dPGJ2, and indomethacin, caused inhibition of prolifera-
tion in several human breast cancer cell lines, such as MCF7,
MDA-MB-231, BT474, and T47D [162]. Troglitazone also
inhibited MCF7 tumor growth in triple-immunodeficient
BNX nude mice [162]. Clay et al. reported that 15dPGJ2and
troglitzaone attenuated cellular proliferation of MDA-MB-
231 by blocking cell cycle progression and inducing apoptosis
[160]. Pretreatment of MDA-MB-231 cells with 15dPGJ2
attenuated the capacity of these cells to induce tumors in
nude mice [160]. Yin et al. showed that treatment of MCF7
with troglitazone also decreased the expression of several
regulators of pRb phosphorylation, such as cyclin D1, CDK4,
CDK6, and CDK2 [158]. pRB is a retinoblastoma tumor
suppressor gene product, and phosphorylated pRB induces
cell cycle progression [163]. Troglitazone induced the G1 cell
cycle arrest by attenuation of pRb phosphorylation, resulting
in inhibition of cell proliferation [158]. Suh et al. showed
that GW7845, synthetic PPARγligand, prevented mammary
carcinogenesis in the rat model that used nitrosomethylurea
as the carcinogen [159]. Mehta et al. also reported that
troglitazone prevented the induction of preneoplastic lesions
by 7, 12-dimethylbenz[a]anthracene in a mouse mammary
gland organ culture model [161]. Moreover, PPARγligands
inhibit the cell proliferation in other types of cancer. PPARγ
ligands inhibited the growth of esophageal squamous car-
cinoma cell lines by inducing G1 arrest associated with an
increased level of several CKIs, such as p27Kip1,p21
Cip1/Waf1,
and p18Ink4c [138]. PPARγligands also induced apoptosis
and G1 cell cycle arrest in human gastric cancer cells,
and that inhibited cell proliferation [139,164]. In human
pancreatic cancer cells, PPARγligands induced apoptosis
and growth inhibition associated with G1 cell cycle arrest
through increasing p27Kip1 protein expression [140,165
167]. In human hepatocellular carcinoma cell lines, PPARγ
ligands induced cell cycle arrest through increased expression
8PPAR Research
of p21Cip1/Waf1,p27
Kip1, and p18Ink4c protein levels [141,
168]. Troglitazone also induced the activation of the cell
death protease, caspase 3, and that induced apoptosis of
human liver cancer cell lines [169]. PPARγis abundantly
expressed in human adrenal tumors including adrenocortical
carcinomas and normal adrenal tissues. PPARγagonists
suppress adrenocortical tumor cell proliferation, increase
apoptosis, and induce adrenal dierentiation [142,170].
Moreover, PPARγligand showed antitumor eect against
human prostate cancer cells and human lung cancer cells
[143,144,171173]. Thus PPARγligands could suppress the
tumorigenesis. Therefore, PPARγligands could be used as
antineoplastic drugs.
In contrast, both troglitazone and rosiglitazone treat-
ment increased the frequency and size of colon tumors
in Apcmin mice [174,175]. Treatment with rosiglitazone
also increased the expression levels of β-catenin, a protein
involved in Wnt signaling and correlating with enhanced
cell proliferation, in the colon of Apcmin mice and HT-29
cells [174]. To investigate the basis for this contradiction,
Girnun et al. used mice heterozygous for PPARγwith both
chemical and genetic models of human colon cancer [176].
Heterozygous loss of PPARγcaused a greater incidence of
colon cancer when these mice were treated with AOM.
Although there was no dierence in β-catenin expression
levels in colorectal tumors between AOM-treated PPARg+/
and wild-type mice, β-catenin expression levels in the
colonic epithelium of untreated PPARg+/mice were greater
than that of untreated wild-type mice. When crossing to
Apc1638Nmice, the mouse model for FAP, there were also no
dierence in β-catenin levels between PPARg+//Apc1638N
and PPARg+/+/Apc1638Nmice before polyp formation. Sur-
vival and the number of tumors formed in the colon also
showed no dierence in both mice. Thus although PPARγ
has the potential to suppress β-catenin levels and colon
carcinogenesis, PPARγhas no eect on β-catenin levels or
tumorigenesis in the presence of APC signaling dysfunction
[176]. Furthermore, PPARγmutations, some of which show
the loss of the transactivation ability, are found in colon
cancers in humans, and that PPARγmay be considered
as a tumor suppressor gene [134]. On the other hand, to
evaluate the contribution of PPARγto breast cancer, Saez
et al. generated transgenic mice, MMTV-VpPPARγmice,
that express a constitutively active form of PPARγin mam-
mary gland [177]. MMTV-VpPPARγmice showed normal
development of mammary gland and no increased ten-
dency to develop tumors. To assess the influence of in-
creased PPARγsignaling on mammary gland neoplasia,
MMTV-VpPPARγmice were crossed to mice that express
a polyoma virus middle T antigen (PyV-MT) in mammary
tissue, MMTV-PyV mice, which rapidly develop tumors.
These mice that expressed both activated PPARγand PyV-
MT showed accelerated development of mammary tumors.
Therefore, although increased PPARγactivation does not
initiate tumor formation in normal mammary tissue, once
a tumor-initiating event occurs, PPARγsignaling serves as a
tumor promoter in the mammary gland. Furthermore, there
is no dierence in tumor development between MMTV-PyV
mice and the mice, generated by crossing PPARg+/mice to
MMTV-PyV mice [177]. Thus in this model, PPARγdoes not
act as a tumor suppressor gene.
Furthermore, PPARγligands exert their biological eects
through a PPARγ-independent pathway. Palakurthi et al.
reported that troglitazone and ciglitazone induced G1 arrest
by inhibiting translation initiation in both PPARg/and
PPARg+/+mouse embryonic stem cells. Thus TZDs inhibit
cell proliferation and tumor growth in a PPARγ-independent
manner [178]. Therefore, although PPARγligands are used
as insulin sensitizers, further investigation is needed to clar-
ify whether PPARγligands are eective chemotherapeutic
agents for cancer in humans.
5. SUMMARY
PPARs are linked to metabolic disorders and are interesting
pharmaceutical targets. Among the synthetic ligands, fibrates
are hypolipidemic compounds that activate PPARα,and
TZDs, which selectively activate PPARγ,arehypoglycaemic
molecules that are used to treat type 2 diabetes. PPARδ
agonists might form eective drugs for obesity, diabetes, and
cardiovascular disease. Moreover, recent evidence suggests
that PPAR modulators may have beneficial eects as chemo-
preventive agents [179]. However, as mentioned above, it
remains unclear whether PPARs act as oncogenes or as
tumor suppressors. From this viewpoint, current strategies
are aimed at reducing the side eects and improving the
ecacy and safety profile of PPAR agonists, termed selec-
tive PPAR modulators (SPPARMs) [180,181]. This model
proposes that SPPARMs bind in distinct manners to the
ligand binding pocket of PPAR and induce distinct confor-
mational changes of the receptor, resulting in dierential
interactions with cofactors according to the combination
of their expression levels in dierent organs. Thus each
SPPARM leads to dierential gene expression and biological
response. However, what kinds of cofactors are recruited
to PPAR by each SPPARM is still unknown. Thus it is
important to identify the cofactor complex for PPAR with
each SPPARM and the expression patterns of cofactors in
various tissues. Furthermore, recent evidence suggests that
the ligand binding protein in the cytosol that transports
ligands into the nucleus is important to modulate the action
of nuclear receptors. Long-chain fatty acids, endogenous
PPAR ligands, are highly hydrophobic and fatty acids are
bound to fatty acid binding proteins (FABPs) in the aqueous
intracellular compartment [182]. FABPs also bind to PPAR
ligands and transport them from the cytosol into the nucleus
[183191]. In the nucleus, FABPs interact directly with
PPARs and deliver ligands to PPARs, and the activity of
PPARs is modulated [186,187,190192]. Recently, Schug
et al. showed that when the cellular retinoic acid binding
protein-II (CRABP-II) expression levels were higher than
FABP5 in the cells, retinoic acid (RA) bound to CRABP-
II. Subsequently, CRABP-II relocated to the nucleus and
delivered RA to RAR, resulting in inhibition of cell pro-
liferation and induction of apoptosis [187,193]. On the
contrary, when the FABP5 to CRABP-II ratio is high, RA
serves as a physiological ligand for PPARδ, which induces
cell survival and proliferation [187,194]. Therefore, it is
Keisuke Tachibana et al. 9
important to identify the cytosolic ligand binding proteins
and the expression levels of the proteins for defining the
physiological eects of ligands. Furthermore, several ligands
exert their biological eects through a PPAR-independent
pathway [195]. Thus further studies are required to elucidate
the role of PPARs for developing new eciently and safety
chemotherapeutic agents for cancer.
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... However, further studies have found that the mechanism of PPAR-γ in regulating tumorigenesis is complex and contradictory. It acts as a tumor suppressor or inducer mainly depending on the specific situation [11,12]. Some studies have confirmed that PPAR-γ agonists play a key role in anti-proliferation, metastasis, angiogenesis, apoptosis, and immune regulation by activating different cancer cells' signal pathways [13,14]. ...
... Still, other studies have shown that PPAR-γ agonists have potential tumorigenic mechanisms, which may be related to cancer type or tumor microenvironment [9]. Based on the difference of tumor cell lines and ligands, the anti-tumor effect of PPAR-γ ligands is PPAR-γ dependent and PPAR-γ independent [12,15]. It makes the design of compounds targeting PPAR-γ very challenging. ...
... The reasons for the above differences in the antitumor activity of these compounds, on the one hand, may be related to the different expression of PPAR-γ in different cell lines; On the other hand, maybe due to the anti-tumor activity of PPAR-γ ligands was PPAR-γdependent or PPAR-γ-independent reported in previous studies [12,33]. ...
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Regulation of PPAR-γ protein activity has anti-tumor effects, both activation, and inhibition. Based on the PPAR-γ protein and previous work in our laboratory, we designed and synthesized a series of 4,5-diazafenylfluorene-rhodanine conjugates and explored their anti-tumor activity and mechanism in vitro. This series of 4,5-diazafenylfluorene-rhodanine conjugates could induce rapid ubiquitin degradation of PPAR-γ to inhibit its function. And the cytotoxicity in vitro showed that these compounds had selective cytotoxicity to several kinds of tumor cells. Among them, the compound YINQ-9 possessed the best activity against melanoma A375 cells, with an IC50 value of 4.11 μM. Further experiments demonstrated that YINQ-9 could affect the A375 cell’s adhesion to the extracellular matrix and induce anoikis by inhibiting the MAPK/ERK pathway and activating the mitochondrial endogenous apoptosis pathway. This series of novel 4,5-diazafenylfluorene-rhodanine conjugates could inhibit the function of PPAR-γ by inducing ubiquitin degradation, thus inducing A375 cells to anoikis. This study provides a new direction for the design of anti-tumor drugs targeting PPAR-γ. Graphical abstract
... PPARγ is found to influence trophoblast syncytialization and differentiation through activation of GCM1 transcription factor leading to expression of hCG [15,16]. In context to trophoblast biology and placental development, the role of PPARβ/δ & PPARγ is very well known as they are involved in hCG synthesis, fatty acid uptake, lipid metabolism [14], and trophoblast growth [15][16][17], differentiation [18], and invasion [16], but the role of PPARα is still unexplored. Other than the role of PPARα in lipid metabolism, its role in tumor progression or suppression has also been observed in few studies [11,12]. ...
... Other than the role of PPARα in lipid metabolism, its role in tumor progression or suppression has also been observed in few studies [11,12]. PPARα seems to display opposite functions in cancer progression, possibly in a cancer-specific manner that promotes or inhibits tumor growth [18][19][20]. In Breast cancer tissue, increased expression of PPARα and arachidonic acid (endogenous PPARα ligand) was found, along with increased cell proliferation and upregulation in cyclin E expression [21]. ...
... Our results showed that PPARα activation led to a significant reduction in cell migration and invasion. Our results were further supported by the studies performed in diverse cell types like the endothelial cells (HUVECs) [59], ovarian cancer cells [38,60], Lung cancer cells (A549) [18], and Ishikawa endometrial cells [43], wherein it was observed that activation of PPARα led to inhibition of cell migration by modulating the expression of p16, CCND1, angiogenesis, Akt phosphorylation, E2F1 and CDKN1A [59][60][61][62]. VEGF, VEGFR, and HIF play a very important role in vasculogenesis and survival under hypoxic conditions [61], while cyclin A, D, p16, and E2F1 are essential components of cell cycle regulation, cell proliferation, and division [62]. ...
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The peroxisome proliferator-activated receptor-alpha (PPARα) is a member of the ligand-dependent nuclear receptor superfamily known for their crucial role in lipid metabolism. The expression and role of PPARα in trophoblast cells are not very well known. Trophoblast invasion is one of the most critical processes required for successful implantation of the developing embryo into the maternal endometrium. Defects in this process are associated with adverse pregnancy outcomes such as FGR(Fetal Growth Restriction), preeclampsia, and choriocarcinoma. In this present study, we investigated the role of the ligand-activated transcription factor, Peroxisome proliferator-activated receptor (PPARα) in regulating trophoblast cell invasion using cell lines and explants-based models. Immunohistological localization of PPARα in human placental tissues showed a gestational variation with relatively low expression at term as compared to early trimester. PCR and Western Blot also confirmed this. Further to delineate the effect of PPAR alpha on trophoblast invasion, EVT derived HTR8/SVneo cell lines were stimulated with PPARα agonist, i.e., fenofibrate (FF). Fenofibrate stimulation led to an increased activation and nuclear translocation of PPARα, followed by reduced migration and invasion of these cells in a matrigel invasion assay (Boyden chamber). PPAR alpha stimulation also led to a reduced MMP-2/9 expression following our previous observation. Thus, we may conclude that PPARα to be playing a very important regulatory role in orchestrating the invasive trophoblast programme and hence it seems plausible for it to be associated with PE, which is often characterized by a shallow trophoblast invasion.
... Moreover, a higher proportion of genes involved in bacterial motility and chemotaxis among the CP group supported the hypothesis of Al-Hebshi et al. (2017) and Zhang et al. (2020), where such attributes might be associated with cancer-related inflammation. Besides, the elevated gene count of prostate cancer, antigen processing and presentation (Jhunjhunwala et al. 2021), pathways in cancer, Nod-like receptor (Saxena and Yeretssian 2014), signaling pathways (Zhao et al. 2021), and peroxisome proliferator-activated receptor (PPAR) signaling (Tachibana et al. 2008;Apostoli et al. 2014) among the CP group had already been documented in tumor progression. Therefore, these genes may be employed among healthy SLT users for determining the tumor risks and oral health. ...
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Oral cavity squamous cell carcinoma (OSCC) is the most common type of head and neck cancer worldwide. Smokeless tobacco (SLT) has been well proven for its role in oral carcinogenesis due to the abundance of several carcinogens. However, the role of inhabitant microorganisms in the oral cavity of smokeless tobacco users has not yet been well explored in the context of OSCC. Therefore, the present investigation was conceived to analyze the oral bacteriome of smokeless tobacco users having OSCC (CP group). With the assistance of illumina-based sequencing of bacterial-specific V3 hypervariable region of 16S rDNA gene, 71,969 OTUs (operational taxonomic units) were categorized into 18 phyla and 166 genera. The overall analysis revealed that the oral bacteriome of the patients with OSCC, who were smokeless tobacco users, was significantly different compared to the healthy smokeless tobacco users (HTC group) and non-users (HI users). The appearance of 14 significantly abundant genera [FDR (false discovery rate) adjusted probability value of significance (p value) < 0.05] among the CP group showed the prevalence of tobacco-specific nitrosamines forming bacteria (Staphylococcus, Fusobacterium, and Campylobacter). The functional attributes of the oral bacteriome of the CP group can also be correlated with the genes involved in oncogenesis. This study is the first report on the oral bacteriome of Indian patients with OSCC who were chronic tobacco chewers. The results of the present study will pave the way to understand the influence of smokeless tobacco on the oral bacteriome of OSCC patients. Key points • Oral bacteriome of OSCC patients differ from healthy smokeless tobacco (SLT) users and SLT non-users. • Smokeless tobacco influences the oral bacteriome of OSCC group. • Oral bacteriome specific diagnostics may be developed for pre-diagnosis of oral cancer.
... PPAR protein family plays a role in processes like the clearance of circulating or cellular lipids via the regulation of gene expression involved in lipid metabolism in liver and skeletal muscle, lipid oxidation and cell proliferation [32]. It has been observed that the PPAR pathway can favour tumour progression through mechanisms such as induction of cell proliferation, inhibition of apoptosis, upregulation of VEGF expression, increased PGE2 production and COX expression [78], the latter responsible for the biosynthesis of prostanoids involved in mitosis and the inflammatory response [79]. ...
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Retinoblastoma (Rb) is a rare intraocular tumour in early childhood, with an approximate incidence of 1 in 18 000 live births. Experimental studies for Rb are complex due to the challenges associated with obtaining a normal retina to contrast with diseased tissue. In this work, we reanalyse a dataset that contains normal retina samples. We identified the individual genes whose expression is different in Rb in contrast with normal tissue, determined the pathways whose global expression pattern is more distant from the global expression observed in normal tissue, and finally, we identified which transcription factors regulate the highest number of differentially expressed genes (DEGs) and proposed as transcriptional master regulators (TMRs). The enrichment of DEGs in the phototransduction and retrograde endocannabinoid signalling pathways could be associated with abnormal behaviour of the processes leading to cellular differentiation and cellular proliferation. On the other hand, the TMRs nuclear receptor subfamily 5 group A member 2 and hepatocyte nuclear factor 4 gamma are involved in hepatocyte differentiation. Therefore, the enrichment of aberrant expression in these transcription factors could suggest an abnormal retina development that could be involved in Rb origin and progression.
... Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/foods11091253/s1, Table S1: Potential human protein targets of isoxanthohumol, References [34,42,49,61,62,[70][71][72][73][74][75][76][77][78] are cited in the Table S1, Table S2: Potential human protein targets of 8-prenylnaringenin, References [61,62,71,79,80] are cited in the Table S2, Table S3: Potential human protein targets of 6-prenylnaringenin, References [75,[81][82][83][84][85][86][87][88][89][90][91] are cited in the Table S3. The predicted docking scores, protein functions, and reported experimental correlations with anticarcinogenic functions for isoxanthohumol, 8-prenylnaringenin, and 6-prenylnaringenin, respectively, are presented in Tables S1-S3. ...
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Natural products from plants exert a promising potential to act as antioxidants, antimicrobials, anti-inflammatory, and anticarcinogenic agents. Xanthohumol, a natural compound from hops, is indeed known for its anticarcinogenic properties. Xanthohumol is converted into three metabolites: isoxanthohumol (non-enzymatically) as well as 8- and 6-prenylnaringenin (enzymatically). An inverse molecular docking approach was applied to xanthohumol and its three metabolites to discern their potential protein targets. The aim of our study was to disclose the potential protein targets of xanthohumol and its metabolites in order to expound on the potential anticarcinogenic mechanisms of xanthohumol based on the found target proteins. The investigated compounds were docked into the predicted binding sites of all human protein structures from the Protein Data Bank, and the best docking poses were examined. Top scoring human protein targets with successfully docked compounds were identified, and their experimental connection with the anticarcinogenic function or cancer was investigated. The obtained results were carefully checked against the existing experimental findings from the scientific literature as well as further validated using retrospective metrics. More than half of the human protein targets of xanthohumol with the highest docking scores have already been connected with the anticarcinogenic function, and four of them (including two important representatives of the matrix metalloproteinase family, MMP-2 and MMP-9) also have a known experimental correlation with xanthohumol. Another important protein target is acyl-protein thioesterase 2, to which xanthohumol, isoxanthohumol, and 6-prenylnaringenin were successfully docked with the lowest docking scores. Moreover, the results for the metabolites show that their most promising protein targets are connected with the anticarcinogenic function as well. We firmly believe that our study can help to elucidate the anticarcinogenic mechanisms of xanthohumol and its metabolites as after consumption, all four compounds can be simultaneously present in the organism.
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Metastasis, in which cancer cells detach from the original site and colonise other organs, is the primary cause of death induced by bladder cancer (BCa). Epithelial Membrane Protein 1 (EMP1) is dysregulated in many human cancers, and its clinical significance and biological function in diseases, including BCa, are largely unclear. Here, we demonstrated that EMP1 was downregulated in BCa cells. The deficiency of EMP1 promotes migration and confers resistance to ferroptosis/oxidative stress in BCa cells, favouring tumour cell metastasis. Mechanistically, we demonstrated that EMP1 deficiency enhanced tumour metastasis by increasing PPARG expression and promoting its activation, leading to upregulation of pFAK(Y397) and SLC7A11, which promoted cell migration and anti-ferroptotic cell death respectively. Moreover, we found EMP1-deficient sensitized cells to PPARG's ligand, which effect are metastatic phenotype promoted and could be mitigated by FABP4 knockdown. In conclusion, our study, for the first time, reveals that EMP1 deficiency promotes BCa cell migration and confers resistance to ferroptosis/oxidative stress, thus promoting metastasis of BCa via PPARG. These results revealed a novel role of EMP1-mediated PPARG in bladder cancer metastasis.
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Diabetes mellitus (DM) has attained the status of a global pandemic. Cardiovascular disease was the leading cause of morbidity in people with type 2 DM, however, a transition from cardiovascular disease to cancer as the leading contributor to DM related death has been observed lately. Multiple myeloma (MM) is the second most common hematological malignancy. Obesity is a common risk factor for both DM and MM. Although data are limited, studies have shown that DM might be associated with increased risk for the development of MM. The presence of DM might affect the course of patients with MM, since hyperglycemia may have an impact on both the efficacy and the adverse effects of antimyeloma therapy. In parallel, DM and MM share common clinical presentations, such as nephropathy, neuropathy, and cardiovascular disease. In terms of antidiabetic medications, metformin might present a synergistic effect with antimyeloma drugs and also prevent some of the adverse effects of these drugs; pioglitazone might have favorable effects when given as add on treatment in people with relapsed or refractory MM. No clinically important interactions have been observed between antidiabetic agents and the most commonly used antimyeloma drugs. Further data are needed to examine the effect of all classes of antidiabetic medication on MM and its complications. A baseline assessment of risk factors for glucose intolerance and close monitoring of glucose levels during therapy is strongly suggested for patients with MM. This article is protected by copyright. All rights reserved.
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The testis expresses peroxisome proliferator-activated receptor-γ (PPAR-γ), but its involvement in regulating diabetes-induced testicular dysfunction and DNA damage repair is not known. Pioglitazone-induced activation of PPAR-γ for 12 weeks in db/db obese diabetic mice increases bodyweights and reduces blood glucose levels, but PPAR-γ inhibition by 2-chloro-5-nitro-N-phenylbenzamide does not alter these parameters; instead, improves testis and epididymis weights and sperm count. Neither activation nor inhibition of PPAR-γ normalizes the diabetes-induced seminiferous epithelial degeneration. The PPAR-γ activation normalizes testicular lipid peroxidation, but its inhibition reduces lipid peroxidation and oxidative DNA damage (8-oxo-dG) in diabetic mice. As a response to diabetes-induced oxidative DNA damage, the base-excision repair (BER) mechanism proteins- 8-oxoguanine DNA glycosylases (OGG1/2) and X-ray repair cross-complementing protein-1 (XRCC1) increase, whereas the redox-factor-1 (REF1), DNA polymerase (pol) δ and poly (ADP-ribose) polymerase-1 (PARP1) show a tendency to increase suggesting an attempt to repair the oxidative DNA damage. The PPAR-γ stimulation inhibits OGG2, DNA pol δ, and XRCC1 in diabetic mice testes, but PPAR-γ inhibition reduces oxidative DNA damage and normalizes BER protein levels. In conclusion, type 2 diabetes negatively affects testicular structure and function and increases oxidative DNA damage and BER protein levels due to increased DNA damage. The PPAR-γ modulation does not significantly affect the structural changes in the testis. The PPAR-γ stimulation aggravates diabetes-induced effects on testis, including oxidative DNA damage and BER proteins, but PPAR-γ inhibition marginally recovers these diabetic effects indicating the involvement of the receptor in the reproductive effects of diabetes.
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Background: Cholangiocarcinoma is a devastating cancer with a poor prognosis. Previous reports have presented conflicting results on the role of transforming growth factor-β-induced protein (TGFBI) in malignant cancers. Currently, our understanding of the role of TGFBI in cholangiocarcinoma is ambiguous. The aim of the present study was to investigate the role of TGFBI in human cholangiocarcinoma. Methods: Iterative patient partitioning (IPP) scoring and consecutive elimination methods were used to select prognostic biomarkers. mRNA and protein expression levels were determined using Gene Expression Omnibus (GEO), Western blot and ELISA analyses. Biological activities of selected biomarkers were examined using both in vitro and in vivo assays. Prognostic values were assessed using Kaplan-Meier and Liptak's z score analyses. Results: TGFBI was selected as a candidate cholangiocarcinoma biomarker. GEO database analysis revealed significantly higher TGFBI mRNA expression levels in cholangiocarcinoma tissues compared to matched normal tissues. TGFBI protein was specifically detected in a soluble form in vitro and in vivo. TGFBI silencing evoked significant anti-cancer effects in vitro. Soluble TGFBI treatment aggravated the malignancy of cholangiocarcinoma cells both in vitro and in vivo through activation of the integrin beta-1 (ITGB1) dependent PPARγ signalling pathway. High TGFBI expression was associated with a poor prognosis in patients with cholangiocarcinoma. Conclusions: Our data suggest that TGFBI may serve as a promising prognostic biomarker and therapeutic target for cholangiocarcinoma.