<p>Recommended by Dipak Panigrahy</p> <p>Decreased expression of peroxisome proliferator activated receptor-<italic>γ</italic> (PPAR<italic>γ</italic>) and high levels of the proinflammatory enzyme cyclooxygenase-2 (COX-2) have been observed in many tumor types. Both reduced (PPAR<italic>γ</italic>) expression and elevated COX-2 within the tumor are associated with poor prognosis in lung cancer patients, and recent work has indicated that these signaling pathways may be interrelated. Synthetic (PPAR<italic>γ</italic>) agonists such as the thiazolidinedione (TZD) class of anti-diabetic drugs can decrease COX-2 levels, inhibit growth of non-small-cell lung cancer (NSCLC) cells in vitro, and block tumor progression in xenograft models. TZDs alter the expression of COX-2 and consequent production of the protumorigenic inflammatory molecule prostaglandin E2 (PGE2) through both (PPAR<italic>γ</italic>) dependent and independent mechanisms. Certain TZDs also reduce expression of PGE2 receptors or upregulate the PGE2 catabolic enzyme 15-prostaglandin dehydrogenase. As several COX-2 enzymatic products have antitumor properties and specific COX-2 inhibition has been associated with increased risk of adverse cardiac events, directly reducing the effects or concentration of PGE2 may provide a more safe and effective strategy for lung cancer treatment. Understanding the mechanisms underlying these effects may be helpful for designing anticancer therapies. This article summarizes recent research on the relationship between (PPAR<italic>γ</italic>), TZDs, and the COX-2/PGE2 pathways in lung cancer.</p>
<p> Despite the many advances made in diagnostic and treatment
strategies, lung cancer remains the leading cause of cancer-related mortality
in the United States and is responsible for more deaths than prostate, colon,
and breast cancers combined [##REF##17237035##1##]. Investigating the molecular mechanisms underlying the
pathogenesis of lung cancer provides opportunities to develop innovative
therapies that may reduce suffering due to this devastating disease. Decreased expression
of peroxisome proliferator activated receptor (PPAR<italic>γ</italic>) originally identified as
a regulator of glucose metabolism and adipocyte differentiation [##UREF##0##2##] has been associated with poor prognosis in lung cancer
patients [##REF##11891036##3##]. PPAR<italic>γ</italic> affects inflammatory
gene expression, cell division, apoptosis, invasion, release of proangiogenic
cytokines, and differentiation in many cancer types including lung cancer [##REF##15799829##4##–##REF##17264754##8##]. These properties have prompted extensive research on PPAR<italic>γ</italic>
in cancer treatment and prevention. 
Members of the thiazolidinedione (TZD) class of PPAR<italic>γ</italic> agonists are
currently approved for treatment of diabetes, and elicit many of the antitumor
properties of PPAR<italic>γ</italic> activation through both PPAR<italic>γ</italic> dependent and independent
pathways [##REF##16499875##9##–##REF##17412838##14##]. Several studies have
demonstrated elevated constitutive expression of the inducible proinflammatory
enzyme, cyclooxygenase-2 (COX-2) in human lung
cancer [##REF##9515807##15##–##REF##11086200##19##]. Mounting evidence from investigations into the molecular
effects of COX-2 over-expression in lung tumor cells indicates that this enzyme
has a multifaceted role in conferring the malignant and metastatic phenotypes. The COX-2 enzymatic product prostaglandin E2 (PGE2) has
been implicated in apoptosis resistance [##REF##8521479##20##–##REF##15374938##22##], angiogenesis [##REF##11032965##23##, ##UREF##2##24##], decreased host immunity [##REF##17312132##25##, ##REF##16034085##26##], and enhanced invasion and metastasis 
[##REF##11320076##27##–##REF##11278548##29##]. This review summarizes investigations in the
relationship between PPAR<italic>γ</italic>,
its ligands, and COX-2 and PGE<sub>2</sub> in lung cancer.</p> <p>The PPAR
family consists of three isoforms: PPAR<italic>α</italic>, PPAR<italic>γ</italic>, and PPAR<italic>δ</italic>, each encoded by
different genes. PPARs are members of
the nuclear hormone class of receptors and are involved in energy metabolism
through transcriptional regulation of specific gene sets. Observations
regarding high PPAR<italic>γ</italic>
expression in adipose tissue in combination with its
role in lipid and glucose homeostasis led to the development of the TZD class
of PPAR<italic>γ</italic>
agonists, including troglitazone, ciglitazone, rosiglitazone, and pioglitazone
as antidiabetic and insulin-sensitizing
drugs. Rosiglitazone and pioglitazone
are currently approved for treatment of type 2 diabetes mellitus [##UREF##3##30##], and this class of drugs has been clinically available for
approximately a decade. Some of the TZDs have been shown to exert anti-inflammatory
[##REF##16218490##31##], antiproliferative [##REF##14657213##32##], and antiangiogenic effects 
[##REF##15799829##4##]. The COX metabolite
15d-PGJ<sub>2</sub> is a natural PPAR<italic>γ</italic> ligand and is considered a negative
regulator of inflammatory and immune responses [##REF##15639643##33##]. More recent results indicating that PPAR<italic>γ</italic> activation may
attenuate inflammatory responses and cancer progression have led to extensive
investigation into the role of this protein in inflammation and carcinogenesis.</p> <p>PPAR<italic>γ</italic> is expressed
in human non-small-cell lung cancer (NSCLC) and small
cell lung carcinoma [##REF##11724309##34##], and the
expression of PPAR<italic>γ</italic> has been
correlated with tumor histological type and grade [##REF##12009233##35##]. In NSCLC,
decreased PPAR<italic>γ</italic> expression
was correlated with poor prognosis [##REF##11891036##3##]. TZDs inhibit 
tumor formation
in a variety of animal models, including colon [##REF##15289864##36##] and lung cancers 
[##REF##14712215##37##], and PPAR<italic>γ</italic> over-expression
protects against tumor development in a mouse model of lung tumorigenesis [##REF##18055759##38##]. Further, 
increased PPAR<italic>γ</italic> activity promotes epithelial differentiation of NSCLC cells in 3D culture 
[##REF##15608671##5##]. It has also been shown that PPAR<italic>γ</italic> inhibits the growth of
NSCLC in vitro and in vivo [##REF##15608671##5##, ##REF##12391285##39##, ##REF##16505118##40##].</p> <p>Cyclooxygenase
is the rate-limiting enzyme for production of prostaglandins and thromboxanes
from free arachidonic acid [##REF##11028754##41##, ##REF##8555245##42##]. Two COX isoforms, COX-1 and
COX-2, have been extensively studied. 
COX-1 is
constitutively expressed in most cells and tissues. COX-2 is an inducible
enzyme that acts to produce prostaglandins and/or thromboxanes during an acute
inflammatory response. The direct enzymatic product of COX-2 and PGH<sub>2</sub> is converted to prostaglandins or
thromboxanes by individual isomerases or prostaglandin synthases, and relative
production of the various COX-2 products depends upon cellular concentrations
of down-stream metabolic and catabolic enzymes within the COX-2 pathway. In NSCLC, the
major eicosanoid produced is prostaglandin E2 (PGE<sub>2</sub>) through microsomal PGE<sub>2</sub> synthase (mPGES) activity. The nicotinamide adenine dinucleotide
positive-dependent catabolic enzyme 15-hydroxyprostaglandin
dehydrogenase (15-PGDH) metabolizes PGE<sub>2</sub> to biologically
inactive 15-keto derivatives. 
The final PGE2 concentration experienced by NSCLC cells depends upon expression of
PGES and 15-PGDH. A large body of evidence indicates that increased PGE2
production contributes to tumorigenesis. COX-2 over-expression is frequently
observed in NSCLC, and the accompanying increased proliferation, invasion,
angiogenesis, and resistance to apoptosis have been attributed in part to elevated PGE<sub>2</sub> production in the vicinity of the tumor. Thus, COX-2
and its downstream signaling pathways represent potential targets for lung
cancer chemoprevention and therapy.</p> <p>Studies
indicate that COX-2 and PPAR<italic>γ</italic> signaling pathways are intertwined. PPAR<italic>γ</italic> ligands suppress
COX-2 expression induced by LPS and PMA in macrophages, astrocytes, and
epithelial cells [##REF##11278336##43##–##REF##11971025##45##]. The COX-2 metabolite 15d-PGJ2 is an endogenous ligand for PPAR<italic>γ</italic> 
[##REF##8521498##46##], and
during resolution of inflammation elevated 15d-PGJ2 production
downregulates COX-2 through a negative feedback loop involving PPAR<italic>γ</italic> and NF-<italic>κ</italic>B [##REF##10827178##44##, ##UREF##4##47##]. Synthetic and endogenous
PPAR<italic>γ</italic> ligands decrease the high COX-2 expression associated with
several malignancies including cervical [##REF##14555539##48##] and liver cancers 
[##REF##12800228##49##] and forced PPAR over-expression decreases COX-2 levels in
lung cancer cells [##REF##18055759##38##]. While PPAR<italic>γ</italic> agonists
decrease COX-2 expression or prevent COX-2 induction in most settings, COX-2
expression is increased in some studies [##UREF##5##50##, ##REF##18162716##51##]. For example, Ikawa et al. reported
that rosiglitazone (also known as BRL49653) increases COX-2 expression in human
colorectal carcinoma cells [##REF##11412039##52##]. PPAR<italic>γ</italic> ligands also have
been shown to induce COX-2 expression in mammary epithelial cells [##REF##10075740##53##], monocytes 
[##REF##11809750##54##], and human synovial fibroblasts [##REF##11840453##55##]. The effect of PPAR<italic>γ</italic>
agonists on COX-2 expression may vary based upon the cell type, the specific
agonist molecule, and the presence of additional inflammatory mediators.
Off-target effects of TZDs may also partially account for differences in the
effects of these molecules on COX-2 expression.</p> <p>Although TZDs are widely known as ligands for PPAR<italic>γ</italic>, they may mediate receptor-independent 
effects,
as previously reported [##UREF##6##56##–##REF##17975488##58##]. For example, 
by using embryonic stem cells from PPAR<italic>γ</italic>-null mice, 
Chawla et al. found that neither
macrophage differentiation nor anti-inflammatory effects of
synthetic PPAR<italic>γ</italic> ligands are PPAR<italic>γ</italic> receptor-dependent. To
distinguish the effects of PPAR<italic>γ</italic> from off-target effects of PPAR<italic>γ</italic> ligands in
lung cancer cells, Bren-Mattison et al.
utilized a molecular approach to over-express PPAR<italic>γ</italic> in two NSCLC cell lines
and assessed the direct effect of PPAR<italic>γ</italic>. Their goal was to determine whether
the antitumorigenic effects of PPAR<italic>γ</italic> were
mediated via COX-2 pathways in NSCLC. Their results clearly demonstrated that exogenously 
expressed
PPAR<italic>γ</italic> suppresses COX-2 promoter activity and protein expression resulting in
suppression of PGE<sub>2</sub> production [##REF##18055759##38##]. The COX-2 
promoter has binding sites for cAMP response
element, NF-IL-6, and NF-<italic>κ</italic>B [##REF##10652293##59##]. Although the COX-2
promoter contains multiple regulatory elements, their data indicate
that the inhibitory effects of PPAR<italic>γ</italic> are mediated through NF-<italic>κ</italic>B.
Several studies have demonstrated that constitutive activation of
NF-<italic>κ</italic>B in tumor cells is mediated through activation of Akt [##REF##10485711##60##, ##REF##10669740##61##]. Bren-Mattison et al. demonstrated that the
inhibitory effects of PPAR<italic>γ</italic> on COX-2 were mediated via increased activity of
PTEN leading to decreased phospho-Akt and inhibition of NF-<italic>κ</italic>
<italic>β</italic> [##REF##18055759##38##]. These authors further demonstrated that transgenic mice
over-expressing PPAR<italic>γ</italic> exhibited reduced COX-2 in type II alveolar epithelial
cells of lung, and those mice were protected against lung cancer development in
a chemical carcinogenesis mouse model [##REF##18055759##38##]. In summary, these data indicate that COX-2 downregulation
may mediate some of the antitumorigenic effects of PPAR<italic>γ</italic> over-expression.</p> <p>The
PPAR<italic>γ</italic> agonists may also affect COX-2 in a PPAR<italic>γ</italic> independent manner (see ##TAB##0##Table 1##). For
example, in A549 NSCLC cells troglitazone enhanced both COX-2 and mPGES expression
in a concentration dependent manner, resulting in a marked increase in PGE<sub>2</sub> production 
[##REF##15993751##62##]. Cotreatment with the PPAR<italic>γ</italic> antagonists
GW9662 and bisphenol A diglycidyl ether (BADGE) had no effect on COX-2
induction by troglitazone indicating that this event is PPAR<italic>γ</italic> independent.
Troglitazone increased COX-2 expression at least in part by activating ERK and PI3K pathways,
which have been previously demonstrated to influence COX-2 levels [##REF##14987993##63##–##REF##11266376##65##]. Combined troglitazone and TNF<italic>α</italic> stimulation resulted in
additive enhancement of COX-2 expression. The COX-2 metabolite 15d-PGJ<sub>2</sub> had no detectable effects on COX-2 or mPGES expression or PGE<sub>2</sub> production in A549 cells. This is consistent with the hypothesis that PPAR<italic>γ</italic>-independent mechanisms can partially account for
discrepancies in the effects of different TZD drugs on COX-2 expression. Thus,
in lung cancer, PPAR<italic>γ</italic> agonists appear to
regulate COX-2 expression and affiliated protumorigenic cellular phenotypes
through both PPAR<italic>γ</italic> dependent and
independent means.</p> <p>We
recently examined the effect of the pioglitazone and rosiglitazone on COX-2 and
PGE<sub>2</sub> levels in A427 and A549 NSCLC cells. Both TZDs inhibited PGE<sub>2</sub> 
production in NSCLC cells via a COX-2 independent pathway. To define
the mechanism underlying COX-2 independent suppression of PGE<sub>2</sub> production, we 
focused on the prostaglandin synthases that are responsible for the PGE<sub>2</sub> 
production and on 15PGDH the catabolic enzyme
responsible for its degradation to biologically inactive15-keto
derivatives [##UREF##7##66##]. None of the three
prostaglandin synthases (microsomal PGES1, PGES2, and cytosolic
PGES) was downregulated by
pioglitazone or rosiglitazone, however, 15-PGDH was induced by TZDs.
TZD-mediated suppression of PGE<sub>2</sub> concentration was
significantly inhibited by small interfering RNA to 15-PGDH. Studies
using dominant-negative PPAR<italic>γ</italic> over-expression or
GW9662 revealed that
the induction
of 15-PGDH by both pioglitazone and rosiglitazone is PPAR<italic>γ</italic>-independent.These findings indicate that it is
possible to use a clinically available pharmacological intervention
to suppress tumor-derived PGE<sub>2</sub> by enhancing catabolism
rather than blocking synthesis. The potential benefits of inhibiting
PGE<sub>2</sub> levels in a COX-2-independent manner include the
following. First, promoting 15-PGDH activity could decrease PGE<sub>2</sub> without modifying other prostaglandins such as PGI<sub>2</sub>. This
is potentially important because the latter has been noted to have
antitumor properties [##REF##15313935##67##]. It has been suggested that a ratio of PGs may be
important in regulating the malignant phenotype. Thus, inhibiting
COX-2 activity would diminish both PGE<sub>2</sub> and PGI<sub>2</sub>,
whereas selective induction of 15-PGDH could lead to a more
favorable PGI<sub>2</sub>/PGE<sub>2</sub> ratio. Second, suppression of PGE<sub>2</sub> levels without alteration in COX-2 may limit
some of the cardiovascular toxicities associated with COX-2
inhibition [##REF##15684210##68##]. Finally, unlike COX-2 inhibition, which may lead
to upregulation of certain leukotrienes that favor malignant progression
[##REF##15501964##69##], 15-PGDH induction may lead only to a decrement
of PGE<sub>2</sub>. This speculation will require further investigation.</p> <p>Different
TZDs have the capacity to modulate arachidonic acid metabolism by a variety of
pathways (see ##FIG##0##Figure 1##). Recent evidence indicates that
ciglitazone induces differentiation and apoptosis in NSCLC [##REF##10706135##7##]. The mechanisms of
ciglitazone's capacity to modulate PGE2 levels in lung adenocarcinoma cells
were recently reported [##UREF##1##13##]. In contrast to pioglitazone and rosiglitazone, ciglitazone
mediates COX-2 dependent suppression of PGE<sub>2</sub> in NSCLC. Ciglitazone
treatment suppressed COX-2 mRNA expression and COX-2 promoter activity but did
not modify the expression of enzymes downstream of COX-2 including PGES and
15-PGDH. Utilization of dominant-negative PPAR<italic>γ</italic> showed that suppression
of COX-2 and PGE2 by ciglitazone is mediated via non-PPAR pathways.</p> <p>PPAR<italic>γ</italic> ligands may also interfere with
protumorigenic signals derived from COX-2 by interrupting the 
function of PGE<sub>2</sub> G-protein coupled receptors (GPCRs) designated E-prostanoid (EP) receptors 1–4 
[##REF##9737710##70##]. Han and Roman found
that in NSCLC cell lines, the PPAR<italic>γ</italic> ligands GW1929, 15 dPGJ<sub>2</sub>, ciglitazone, troglitazone, and rosiglitazone significantly decreased EP2 mRNA and
protein levels causing growth inhibition in NSCLC cells [##REF##14751245##71##]. The inhibitory effects of rosiglitazone and ciglitazone but
not 15d-PGJ2 were suppressed by the PPAR<italic>γ</italic> antagonist GW9662
suggesting the involvement of PPAR<italic>γ</italic>-dependent and independent mechanisms.</p> <p>Recently, a retrospective study by Govindarajan et al. demonstrated a significant reduction in lung cancer
risk in diabetic patients using the TZD rosiglitazone [##REF##17442990##72##]. Importantly, several clinical studies in diabetes patients
have demonstrated an increased risk of cardiovascular events associated with rosiglitazone or
pioglitazone treatment [##REF##17687124##73##–##REF##17517853##75##]. This is of particular significance in light
of cardiovascular toxicity associated with COX-2 inhibition. Recently, several chemoprevention trials
are being initiated using TZDs [##UREF##8##76##]. However, adverse cardiac events are associated
with chronic TZD treatment [##REF##17637582##74##]. Based
on these findings, future clinical studies attempting to utilize TZDs in
prevention of cancer will require selection of patient populations without
cardiovascular risk. Prospective
clinical studies specifically designed to address the effects of TZDs on cancer,
and cardiac outcomes are required. If the anti-inflammatory and antitumor effects of TZDs are derived
through pathways distinct from those leading to cardiovascular toxicity, more
selective candidate drug molecules may be therapeutically effective, without
leading to adverse cardiac events. Thus, more research is required to define
opportunities to specifically interfere with PGE<sub>2</sub> production,
metabolism, or downstream effects. This could ultimately lead to reduction in
lung cancer growth or prevention while leaving the steady-state concentrations
of desirable eicosanoids in tact [##REF##17944566##77##].</p> <p>Both elevated COX-2 and reduced PPAR<italic>γ</italic> expression are
associated with poor prognosis in lung cancer patients [##REF##11891036##3##, ##REF##14568683##78##–##REF##16996907##80##] and recent work has revealed multiple interactions between
PPAR<italic>γ</italic> signaling and the COX-2 pathway. 
The COX-2 product 15d-PGJ<sub>2</sub> is an endogenous ligand for PPAR<italic>γ</italic>,
and PPAR<italic>γ</italic> activation as a result of elevated 15d-PGJ<sub>2</sub> results in
COX-2 downregulation in an autoregulatory feedback loop that may contribute to
natural resolution of the inflammatory response [##REF##8521498##46##]. 
Forced expression of PPAR<italic>γ</italic> decreases COX-2 expression in cultured human
NSCLC cells and mouse lungs and protects against lung tumor development in a
murine model [##REF##15608671##5##, ##REF##18055759##38##]. Synthetic PPAR<italic>γ</italic> ligands, several of
which are currently approved for treatment of diabetes, can interrupt several
stages of the COX-2/PGE<sub>2</sub> protumorigenic pathway, although in certain
cases PPAR<italic>γ</italic> ligands may increase COX-2 expression. These effects are primarily mediated through
PPAR<italic>γ</italic>-independent pathways (see ##TAB##0##Table 1##). 
PPAR<italic>γ</italic> ligands may directly decrease COX-2 transcription in an NF-<italic>κ</italic>B-dependent manner [##REF##18055759##38##], or they can interfere with downstream
targets such as the PGE<sub>2</sub> receptor EP2 [##REF##14751245##71##] or the enzyme responsible for PGE2
catabolism, 15-PGDH [##UREF##7##66##]. 
The targets downstream of COX-2 may be useful in light of recent
evidence that interfering with COX-2 enzymatic activity may increase risk of
cardiovascular events [##REF##15684210##68##]. 
The discovery that certain PPAR<italic>γ</italic> agonists can specifically reduce PGE<sub>2</sub> concentration or expression of EP receptors may aid in the design of strategies
to reduce the effects of harmful prostaglandins without impacting production of
critical cardioprotective eicosanoids.</p>
<fig id="fig1" position="float"><label>Figure 1</label><caption><p>Effects of various TZDs on the PGE2
pathway.</p></caption></fig>
<table-wrap id="tab1" position="float"><label>Table 1</label><caption><p>Off-target effects of TZDs in NSCLC.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1"> Thiazolidinediones</th><th align="center" rowspan="1" colspan="1"> Molecular effects</th><th align="left" rowspan="1" colspan="1"> Mechanisms </th><th align="center" rowspan="1" colspan="1"> Reference </th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Troglitazone</td><td align="center" rowspan="1" colspan="1">↑ PGE2</td><td align="left" rowspan="1" colspan="1">↑ COX-2, ERK and PI3K phosphorylation</td><td align="center" rowspan="1" colspan="1">
[##REF##15993751##62##]</td></tr><tr><td align="left" rowspan="1" colspan="1">Pioglitazone, Rosiglitazone</td><td align="center" rowspan="1" colspan="1">↓ PGE2</td><td align="left" rowspan="1" colspan="1">↑ 15-PGDH</td><td align="center" rowspan="1" colspan="1">
[##REF##17412838##14##]</td></tr><tr><td align="left" rowspan="1" colspan="1">Ciglitazone</td><td align="center" rowspan="1" colspan="1">↓ PGE2</td><td align="left" rowspan="1" colspan="1">↓ COX-2</td><td align="center" rowspan="1" colspan="1">
[##UREF##1##13##]</td></tr></tbody></table></table-wrap>
<graphic xlink:href="PPAR2008-790568.001"/>
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PPAR Res. 2008 Aug 27; 2008:790568