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Cancer Bi ol ogy & Ther apy
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Ant i t um or act i vi t y of a PPARδ ant agoni st
Jaseena El i kkot t i l , Di vyanshoo R Kohl i & Kal pna Gupt a
Publ i shed onl i ne: 01 Jul 2009.
To ci t e t hi s art i cl e: Jaseena El i kkot t i l , Di vyanshoo R Kohl i & Kal pna Gupt a ( 2009) Ant i t um or act i vi t y of a PPARδ ant agoni st ,
Cancer Bi ol ogy & Ther apy , 8: 13, 1262- 1264, DOI : 10. 4161/cbt . 8. 13. 9061
To l i nk t o t hi s art i cl e: ht t p: //dx. doi . or g/10. 4161/cbt . 8. 13. 9061
PLEASE SCROLL DOW N FOR ARTICLE
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Peroxisome proliferator-activated receptors (PPARs) are nuclear
receptors (NRs) originally identified by their ability to mediate
the transcriptional effects of peroxisome proliferators.1,2 The three
isotypes of these ligand-activated transcription factors, (PPARα,
γ and δ) display distinct tissue distribution and some overlap-
ping functions.3 Ligand-bound PPARs form heterodimers with
the retinoid X receptor (RXR) and exert their effects by binding
to the peroxisome proliferator response elements (PPREs) in the
promoter regions of target genes to activate transcription. A large
body of evidence has documented important roles of the PPARs
in lipid and glucose homeostasis and the pathogenesis of several
human diseases such as hyperlipidemia, diabetes and obesity.4 In
addition, PPARγ and PPARδ are involved in developmental and
differentiation pathways and therefore play important roles in
embryogenesis, inflammation and cancer.
PPARα is mainly expressed in liver hepatocytes, controls lipid
catabolism, and is well known as the target for the hyperlipidemic
fibrate class of drugs. PPARγ is predominantly expressed in adipose
tissue and plays an important role in adipocyte differentiation and
glucose homeostasis and is the target for the insulin sensitizing
drugs, the glitazones. In contrast, PPARδ is ubiquitously expressed
in most cells and also controls lipid and glucose metabolism, cell
differentiation, motility and proliferation.5,6 All three PPARs
function as lipid sensors and are activated by a diverse group of
lipophilic compounds, including long-chain fatty acids, prosta-
glandins and leukotrienes.1
Whereas PPARα and PPARγ have been extensively studied,
the physiological, cellular and molecular functions of PPARδ have
until recently remained relatively elusive. PPARδ has received
significant attention for its role in energy balance and metabo-
lism.7,8 PPARδ has been explored extensively as a drug target for
metabolic syndrome diseases such as dyslipidemias, obesity and
type-2 diabetes (reviewed in ref. 9). The underlying mechanism(s),
in part, involves the capacity of PPARδ to sense lipids and induce
the expression of specific lipid metabolizing genes10 and energy
uncoupling genes in adipose tissue and muscle.11,12 PPARδ has also
been implicated in embryonic development, inflammation, wound
healing, cell survival, differentiation and proliferation.6,13-16
Although the role of PPARδ in cancer remains controversial,
a growing number of reports suggest that this ubiquitous tran-
scription factor is involved in malignancies of the colon, head
and neck, mammary, hepatocellular, cholangio-, ovarian and
endometrial carcinomas. Several studies have shown that PPARδ
agonists, PPARδ overexpression and PPARδ genetic knockout
inhibit the proliferation, survival and growth of tumors in murine
models.13,17-24 On the other hand, other studies have reported
tumor-inhibiting effects by PPARδ agonists,25-28 while still others
suggest no correlation between PPARδ and tumor progression.29
However, there are now numerous reports implicating PPARδ
in the activation of various pro-survival and proliferative genes,
in various cell types (stem and progenitor cells, vascular smooth
muscle cells, endothelial cells, epithelial cells) that suggest that
PPARδ may play a facilitatory, but key role in pro-oncogenic
signaling and tumorigenesis (see Glazer et al.30) and that PPARδ
antagonists may show inhibition of these processes and subse-
quent antitumor activity. Zaveri et al. in this issue of Cancer
Biology & Therapy report the characterization of a new class of
PPARδ ligands, which block PPARδ agonist-mediated transacti-
vation in reporter screening assays.31 This new ligand, SR13904,
blocked reporter gene expression induced by PPARδ agonists
GW501516,32,33 as well as VLDL,34 suggesting that it may act as a
functional PPARδ antagonist. It is interesting, however, that these
authors show that SR13904 inhibits in vitro tumor cell prolif-
eration of the non-small cell lung cancer (NSCLC) cell line A549
and the Huh7 liver carcinoma cell line, at concentrations that
are consistent with the inhibitory concentrations in the reporter
transactivation assays. At these concentrations, they further show
that SR13904 inhibits the cell cycle in the G1 phase and inhibits
several cell cycle-related proteins, at least one of which (CDK2) is
known to contain PPARδ response elements in its promoter and
is linked to PPARδ.35
*Correspondence to: Kalpna Gupta; Kalpna Gupta; MMC 480, 420 Delaware
St. SE; 8-13 Eikkottil 2879; University of Minnesota Medical School; Minneapolis,
MN 55455 USA; Tel.: 612.624.0123; Fax: 612.625.6919; Email: gupta014@
Submitted: 04/08/09; Accepted: 05/20/09
Previously published online as a Cancer Biology & Therapy E-publication:
Commentary to: Zaveri NT, Sato BG, Jiang F, Calaoagan J, Laderoute KR, Murphy
BJ. A novel peroxisome proliferator-activated receptor delta antagonist, SR13904,
has anti-proliferative activity in human cancer cells. Cancer Biol Ther 2009; This
Antitumor activity of a PPARδ antagonist
Jaseena Elikkottil, Divyanshoo R. Kohli and Kalpna Gupta*
Vascular Biology Center; Division of Hematology Oncology and Transplantation; Department of Medicine; University of Minnesota Medical School; Minneapolis, MN USA
Key words: PPAR, cancer, cell cycle, cell survival, cyclins
[Cancer Biology & Therapy 8:13, 1262-1264; 1 July 2009]; ©2009 Landes Bioscience
1262Cancer Biology & Therapy 2009; Vol. 8 Issue 13
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www.landesbioscience.com Cancer Biology & Therapy1263
PPARδ: Therapeutic target in cancer?
at the same time. The novel small-molecule SR13904 developed
by Zaveri et al. provides a unique advantage of targeting PPARδ,
which is central to the activation of growth and survival promoting
signaling (Fig. 1). Growth inhibition of NSCLC and liver cancer
cells by SR13904 provides a proof of principle that PPARδ plays
a cardinal role in the proliferation and survival of cancer cells. The
PPARδ antagonistic activity of SR13904 will be useful in exam-
ining the role of PPARδ in cancer-promoting signaling and tumor
progression. Furthermore, PPARδ could be exploited as a novel
therapeutic target in cancer. This publication initiates the advent of
a promising new class of small molecules with therapeutic potential
to treat cancer. The novel observations reported by Zaveri et al.
have prepared the stage to launch the examination of PPARδ as a
possible target to treat cancer.
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and independent effects on macrophage-gene expression in lipid metabolism and inflam-
mation. Nat Med 2001; 7:48-52.
2. Escher P, Wahli W. Peroxisome proliferator-activated receptors: insight into multiple
cellular functions. Mutat Res 2000; 448:121-38.
3. Lee CH, Olson P, Evans RM. Minireview: lipid metabolism, metabolic diseases and
peroxisome proliferator-activated receptors. Endocrinology 2003; 144:2201-7.
4. Zaveri NT, Murphy BM. Nuclear Hormone Receptors. In: Taylor J, Triggle D, eds.
Comprehensive Medicinal Chemistry: Elsevier 2007; 993-1036.
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While the involvement of PPARδ in colorectal
cancer is implicated in many studies,13,22,36-38
its involvement in lung carcinoma cell growth is
still controversial. Fukumoto et al. demonstrated
inhibition of A549 lung cancer cell growth in
response to L-165041, a PPARδ/γ agonist,39
whereas He et al. recently showed that the PPARδ
agonist GW501516 has no effect on A549 cell
proliferation.40 On the other hand, several reports
show that activation of PPARδ with GW501516
stimulated NSCLC growth through upregulation
of the prostaglandin E2 receptor EP4 and down-
regulation of PTEN.41 In a recent report, this
same group further delineated the cellular mecha-
nisms for the GW501516-mediated activation
of NSCLC growth and confirmed that PPARδ
activation by GW501516 induces proliferation
of NSCLC cells through inhibition of PTEN via
the activation of the PI3K and NKκB pathways.42
Although the report by Zaveri et al. do not report
investigations with PTEN/PI3K/Akt pathway,
the inhibition of A549 NSCLC cell proliferation
and cell cycle arrest with the PPARδ antagonist
SR13904 and the presence of higher levels of
PPARδ protein in A549 NSCLC cells, appears to
suggest that PPARδ activation may be involved in
tumor cell proliferation of this cell type.
Several oncogenic signaling pathways have been now shown
to involve PPARδ either directly or through its gene targets and
context-dependent feedback loops. For example, the induction
of COX-2 expression by PPARδ can increase PGE2 synthesis,
which in turn can activate protumorigenic signaling through
PI3K/PTEN/Akt/mTOR and production of AA, a PPARδ
agonist.23,24,43 PPARδ also increases the expression of the PGE2
receptor, EP4, which can activate pro-tumorigenic signaling
through the PI3K pathway.41 PPARδ, PGE2 and the PI3K/Akt
pathways exert tumorigenic actions, in part, through antiapop-
totic mechanisms.44,45 A recent report showing that Twist-1 is a
PPARδ-inducible transcription factor46 further underscores the
importance of PPARδ in malignant transformation by COX-2.
Twist-1 is well-known for its role in tumor cell invasion and
metastasis and in inducing an epithelial-mesenchymal transition in
epithelial cells.47-49 Figure 1 represents an overview of the current
understanding of the various PPARδ signaling pathways involved
in tumor promotion and development.
Along with other studies that have shown increased tumor cell
growth associated with PPARδ activation in breast, colon and pros-
tate tumor cells, it is clear that PPARδ plays a role in cell survival,
oncogenic signaling and malignant transformation in many tumor
cell types. The manuscript by Zaveri et al. clearly demonstrates
the antitumor activity of the PPARδ antagonist SR13904 on lung,
liver and breast cancer cell lines. The results show inhibition of
cell cycle progression, cell proliferation and colony formation,
and increased apoptosis. PPARs, being transcriptional regulators,
have the potential to influence multiple intracellular pathways
Figure 1. Signaling mechanisms for PPARδ regulation of cellular proliferation, survival and
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1264 Cancer Biology & Therapy2009; Vol. 8 Issue 13
PPARδ: Therapeutic target in cancer?
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