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Departments of Pharmacology (Y.W., N.S., M.B.S.) and Chemistry
(T.H., G.W.G.) Dartmouth Medical School and Dartmouth College
Hanover, New Hampshire 03755
Howard Hughes Medical Institute
and Departments of Pharmacology and Biochemistry (W.W.P., D.J.M)
University of Texas Southwestern Medical Center Dallas, Texas
75390
Departments of Molecular Biochemistry (L.M.L., S.G.B.),
Molecular Endocrinology (K.D.P.), and Medicinal Chemistry (T.M.W.)
Glaxo Wellcome Research and Development Research Triangle Park,
North Carolina 27709
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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(PPAR). CDDO induces
adipocytic differentiation in 3T3-L1 cells, although it is not as
potent as the full agonist of PPAR, rosiglitazone. Binding studies
of CDDO to PPAR using a scintillation proximity assay give a
Ki between 10-8 to
10-7 M. In
transactivation assays, CDDO is a partial agonist for PPAR. The
methyl ester of CDDO, CDDO-Me, binds to PPAR with similar affinity,
but is an antagonist. Like other PPAR ligands, CDDO synergizes with
a retinoid X receptor (RXR)-specific ligand to induce 3T3-L1
differentiation, while CDDO-Me is an antagonist in this assay. The
partial agonism of CDDO and the antagonism of CDDO-Me reflect the
differences in their capacity to recruit or displace cofactors of
transcriptional regulation; CDDO and rosiglitazone both release the
nuclear receptor corepressor, NCoR, from PPAR, while CDDO-Me does
not. The differences between CDDO and rosiglitazone as either partial
or full agonists, respectively, are seen in the weaker ability of CDDO
to recruit the coactivator CREB-binding protein, CBP, to PPAR. Our
results establish the triterpenoid CDDO as a member of a new class of
PPAR ligands. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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), is not only
antiinflammatory, but also has potent antiproliferative and
differentiating activities (7, 8).
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(PPAR) such as the
thiazolidinedione, rosiglitazone, have also been identified as potent
inducers of adipogenic differentiation (10, 11, 12).
PPAR is a member of the nuclear receptor superfamily of
transcription factors. It forms heterodimers with the retinoid X
receptor (RXR) to activate gene transcription (13, 14, 15). This
cooperation is reflected in the ability of PPAR and RXR ligands to
synergize in the induction of adipocyte differentiation (16).
Furthermore, binding of ligands to nuclear receptors such as PPAR
results in the recruitment or displacement of different cofactors that
either enhance or suppress transcription (17). In particular, the
binding of an agonist to nuclear receptors results in the recruitment
of coactivators such as NCoA/SRC-1 (nuclear receptor
coactivator/steroid receptor coactivator-1) and p300/CBP (CREB binding
protein) and leads to activation of transcription (18, 19). In
contrast, corepressors such as NCoR (nuclear receptor corepressor) or
SMRT (silencing mediator for retinoid and thyroid hormone receptors)
can suppress transcription by binding to receptors either in the
absence of their ligands or when an antagonist is bound (20, 21).
Here we demonstrate that the adipogenic effect of CDDO is due to its
binding to PPAR. It not only induces differentiation as a single
agent, but also acts synergistically with an RXR-specific ligand.
Binding and transactivation studies indicate that CDDO is a partial
agonist for PPAR. We also report that the C-28 methyl ester of CDDO,
CDDO-Me (6, 7), is a PPAR antagonist, and that these opposite
activities of CDDO and CDDO-Me can be explained by their differential
effects on the interactions of cofactors with PPAR.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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), or
rosiglitazone at 100 nM (Fig. 2E) or 1 µM
(Fig. 2F) for 2 days. Accumulation of triglyceride droplets was evident
on the sixth day, as shown by positive staining with Oil Red O.
Treatment with CDDO (100 nM), however, induced
differentiation more slowly and less effectively (Fig. 2C); the
percentage of differentiated cells was approximately 30% by day 6
(Fig. 2C) and peaked at 50% by day 8 (not shown). Interestingly,
unlike rosiglitazone at 1 µM (Fig. 2F), a higher dose of
CDDO (1 µM) was not effective (Fig. 2D), even when
evaluated at day 10. In fact, this higher dose was inhibitory to
differentiation induced by MDI or rosiglitazone (data not shown).
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, which confirms
that CDDO is a weaker inducer than MDI or rosiglitazone, and that it
has no adipogenic activity at 1 µM. The C-28 methyl ester
of CDDO, CDDO-Me, did not induce differentiation in 3T3-L1 cells at all
concentrations tested on day 8 (Fig. 3B). Furthermore, it acted in a
dose-dependent manner as an antagonist and inhibited differentiation
induced by 100 nM rosiglitazone (Fig. 3B). Even though CDDO
also inhibits differentiation at 1 µM, at concentrations
where it acted as a differentiating agent (100 nM or
lower), it did not inhibit differentiation induced by rosiglitazone and
its activity was additive to that of the full agonist (data not
shown).
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. Therefore, binding studies were performed using a
scintillation proximity assay (SPA), which has been successfully used
in the study of PPARs and their ligands (23). Using this assay, CDDO
and rosiglitazone were shown to compete for bound
3H-CDDO, with Ki values of
310 nM and 50 nM, respectively (Fig. 4). Importantly, the presence of
dithiothreitol (DTT) in the binding buffer interfered with CDDO binding
to PPAR. We repeated these experiments using
3H-rosiglitazone as the ligand and nonradioactive
CDDO or CDDO-Me as competitors. Again, the presence of DTT blocked the
ability of either CDDO or CDDO-Me to compete for binding to PPAR;
the Ki values in this assay were determined to be
12 nM for CDDO and 130 nM for CDDO-Me (Fig. 5 and Table 1). Both triterpenoids were also tested
for binding to PPAR
, either in the presence or absence of DTT, and
neither binds to PPAR (Table 1).
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, a
Gal4-PPAR chimeric protein was used to drive the expression of
secreted placental alkaline phosphatase (SPAP) linked to the DNA
binding sequence of Gal4. Figure 6A shows
that CDDO transactivates Gal4-PPAR in a dose-dependent manner,
although the maximal level of transactivation achieved by CDDO was only
26% of that obtained with rosiglitazone (1 µM). We also
tested the ability of CDDO to transactivate the wild-type PPAR
receptor in the context of a natural PPAR response element (PPRE)
derived from the acyl-CoA oxidase gene promoter (13). CDDO had 57% of
the maximal activity obtained with 1 µM rosiglitazone in
this system (Fig. 6B). CDDO-Me, which also bound to PPAR with high
affinity, did not transactivate PPAR in either system (data not
shown). To ensure the specificity of this transactivation, CDDO,
rosiglitazone, and another PPAR ligand,
15-deoxy-
12,14-PGJ2
(15d-PGJ2) (24, 25), were tested in a
transactivation assay for PPAR. While the PPAR ligand Wy14,643
transactivated this receptor, none of the PPAR ligands did (data not
shown). This result is consistent with the fact that CDDO does not bind
to PPAR (Table 1
).
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. Since PPAR is known to heterodimerize with RXR and activate
transcription (13, 26), we determined if CDDO would synergize with the
RXR-specific ligand LG100268 (27). Figure 7 shows that although LG100268 alone at 1
µM induced only slight differentiation in 3T3-L1 cells,
it greatly potentiates the activity of CDDO. In contrast, not only did
CDDO-Me fail to synergize with LG100268 to induce differentiation, it
inhibited the differentiation induced by the RXR ligand (Fig. 7).
Unlike the GPDH assays for CDDO in Fig. 3A, this experiment was
performed on day 6 to minimize the differentiating effect of CDDO and
maximize the level of synergism between CDDO and LG100268.
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or to release the
corepressor, NCoR, from it; rosiglitazone is known to have both of
these activities (28). Figure 8A shows
that rosiglitazone recruits CBP to PPAR in a dose-dependent manner,
as expressed by the level of expression of the reporter gene
chloramphenicol acetyltransferase (CAT) normalized against ß-gal
activity. CDDO also recruits CBP to PPAR in a dose-dependent manner,
but much less so than rosiglitazone. CDDO-Me is also a weaker recruiter
of CBP in the concentrations tested. A maximum of 0.3 µM
CDDO-Me was used since 1 µM CDDO-Me was toxic to the
COS-1 cells used in the transfection assay. We then tested the ability
of PPAR, when bound with CDDO and CDDO-Me, to interact with the
corepressor NCoR. Unlike coactivators, the two-hybrid system indicates
that NCoR interacts with PPAR in the absence of ligands (28). When
rosiglitazone was added, however, NCoR was released from PPAR in a
dose-dependent manner (Fig. 8B), leading to a decrease in CAT reporter
expression. Interestingly, CDDO, although only a partial agonist, was
equally capable of releasing NCoR from PPAR (Fig. 8B). CDDO-Me,
which does not transactivate PPAR, did not lead to a dissociation of
the corepressor (Fig. 8B).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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ligand such as rosiglitazone.
Binding competition assays, using labeled CDDO or rosiglitazone,
indicate that CDDO is a ligand for PPAR, and that this binding could
transactivate both the Gal4-PPAR chimeric and wild-type receptor.
The functional interaction of CDDO with PPAR has been further
confirmed by the ability of CDDO to synergize with a ligand specific
for RXR; RXR and PPAR are known to form functional heterodimers
(13). Further studies on cofactor interactions are consistent with the
observation that CDDO is a partial agonist for PPAR and that its
methyl ester is an antagonist.
Two interesting observations in this study warrant further discussion.
One is the biphasic dose response of CDDO in the induction of 3T3-L1
differentiation. At 1 µM, CDDO not only failed to induce
differentiation (Fig. 3A), but it could also inhibit those induced by
all other known inducers tested, including MDI, rosiglitazone, or
RXR-specific ligands (data not shown); the mechanism of this inhibition
is unknown. However, based on our studies of CDDO in different
biological systems (8), CDDO was shown to be a multifunctional molecule
and could be interacting with cellular targets other than PPAR to
inhibit the differentiation process. This characteristic is not unique
to CDDO. Recent studies of another well known PPAR ligand,
15-deoxy-12,14-PGJ2
(15d-PGJ2), indicate the presence of other
cellular targets, namely components of the nuclear factor-
B (NF-B
pathway), for this prostaglandin (29, 30). The antiinflammatory
activities of 15d-PGJ2, in terms of its ability
to suppress reporter expression driven by NF-B or AP-1 elements,
have been shown to be dependent on PPAR (30).
The second observation is the different binding conditions CDDO and
rosiglitazone require in the in vitro binding studies.
Unlike the results obtained with rosiglitazone, the presence of DTT
interfered with the binding of CDDO to PPAR. Due to the presence of
an ,ß-unsaturated carbonyl function in the A-ring of CDDO, we
searched for direct adduct formation between CDDO and DTT but found
none. Although we could demonstrate no covalent bond formation between
CDDO and DTT, it is still possible that a reversible noncovalent
interaction exists. Again, this sensitivity to DTT is not unique to
CDDO. 15d-PGJ2 has also been shown to be
sensitive to thiol groups found in DTT or cysteine (29, 30), although
there is no convincing chemical evidence to support the notion that a
covalent adduct is found between 15d-PGJ2 and
these agents.
The molecular coordinates of the interaction of CDDO with PPAR
remain to be determined. It would appear that a free –COOH group at
C-28 is important for agonistic activity in the 3T3-L1 cells, since the
methyl ester of CDDO acts as an antagonist in this system. Thus, in
3T3-L1 cells, we have shown that CDDO-Me can block the differentiating
effects of rosiglitazone and the RXR-specific ligand, LG100268, as well
as those of CDDO itself (data not shown). Although CDDO-Me binds to
PPAR, it does not transactivate the receptor, which may be the
result of its failure to cause release of a corepressor such as NCoR.
Given the fact that CDDO is also an inhibitor of differentiation at 1
µM, the mechanisms of the inhibitory actions of CDDO-Me
at the same concentration could be attributed to either a direct
antagonism of PPAR, other mechanisms independent of this receptor,
or both. It is also important to note that at concentrations higher
than 1 µM, CDDO-Me becomes toxic to many cells and thus
should not be used at those doses to attribute the activities to the
antagonism of PPAR.
Although the results we described here provide a reasonable
explanation for the differentiating effects of CDDO on 3T3-L1 cells,
they do not account for other notable activities of CDDO, particularly
its ability to suppress the expression of the enzyme iNOS in
macrophages. Neither do they explain the ability of CDDO to act as a
potent antiproliferative agent on a wide variety of tumor cells or to
induce differentiation in leukemia cells. Thus, we have found that
while CDDO can suppress iNOS expression in macrophages at doses below 1
nM, a number of PPAR ligands, including rosiglitazone
and 15d-PGJ2, are inactive in this assay
at concentrations below 1 µM (our unpublished data and
Refs. 31, 32). Furthermore, unlike CDDO, thiazolidinediones such as
rosiglitazone do not induce differentiation in leukemia cells (our
unpublished data). Given the diverse biological activities of CDDO in
these systems, we are therefore left with the conclusion that it is
likely that another functional receptor system (or systems) beyond
PPAR remain to be identified for CDDO, if we wish to understand the
mechanism of action of this agent in cells other than 3T3-L1. The
identification of PPAR as a receptor for CDDO represents the first
important step in our understanding of the actions of CDDO, but it is
only a beginning in this intriguing problem.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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, pCMX-mPPAR1, PPREx3-tk-Luc
(13); pSG5-Gal4-mPPAR-LBD, pCMX-Gal4-mPPAR1-LBD,
MLH100x4-tk-Luc (25); and Gal4-CBP, Gal4-NCoR, VP16-PPAR2 (28) have
been previously described. 1-Methyl-3-isobutyl xanthine, dexamethasone,
ß-nicotinamide adenine dinucleotide (NADH), and dihydroxyacetone
phosphate (DHAP) were obtained from Sigma (St. Louis, MO).
Insulin was purchased from Biofluids (Rockville, MD).
LG100268 was obtained from Dr. Richard Heyman (Ligand Pharmaceuticals, Inc., San Diego, CA). Reagents for SPA
assays have been described (34).
3T3-L1 Differentiation and Analysis
3T3-L1 cells were obtained from Dr. Gustav Lienhard (Dartmouth
Medical School, Hanover, NH). Cells were propagated in DMEM/5% calf
serum (CS) and differentiated in DMEM/10% FBS. Cells grown to
confluency (day -2) were kept for two more days before agents were
added (day 0). For MDI treatment, 0.5 mM
1-methyl-3-isobutyl xanthine, 0.25 µM dexamethasone, and
0.35 µM insulin were used for 2 days. Cells were then
cultured in DMEM/10% FBS/insulin for the rest of the differentiation
process. All other treatments are for day 0 to day 2 only, and medium
was changed every 2 days. For Oil Red O staining, cells were fixed in
10% formaldehyde for 1 h and stained with Oil Red O for 2 h.
The nuclei were counterstained with hematoxylin and photographed. Lysis
buffer for GPDH analysis includes 50 mM Tris, pH 8, 100
mM NaCl, 0.5% NP-40, 1 mM DTT and was
supplemented with 1 mM phenylmethylsulfonylfluoride, 10
µg/ml each of leupeptin and aprotinin. GPDH enzyme activity was
measured as the consumption of 0.2 mM NADH at 340
nM using 0.2 mM DHAP as the substrate (22).
Transfection Assays
For Gal4-PPAR transactivation studies, CV-1 cells were
transfected as described previously (28). Wild-type PPAR
transfections were performed in HeLa cells using Lipofectamine Plus
(Life Technologies, Inc., Gaithersburg, MD) according to
manufacturer’s instructions. Percentage of transactivation was
normalized against 1 µM rosiglitazone. For mammalian
two-hybrid assays, COS-1 cells in 24-well plates were transfected using
Lipofectamine Plus. Twenty nanograms of CMX-ß-gal, 60 ng pG5-CAT, 60
ng VP16-PPAR2, and 60 ng Gal4-cofactors were used for each well.
Ligands were added 4 h after transfection; CAT and ß-gal
activities were measured 40 h later.
SPA Binding Assays
The details of SPA assays have been published elsewhere (34). In
brief, human PPAR ligand-binding domain was expressed in
Escherichia coli as a polyhistidine-tagged fusion protein.
The protein was purified, biotinylated, and immobilized on
streptavidin-modified SPA beads. DTT was washed away and binding assays
were performed in 50 mM HEPES, pH 7, 50
mM KCl, 5 mM
3-[(3-cholamidopropyl)dimethylammonio]-1-propane sulfonate (CHAPS),
and 0.1 mg/ml BSA. When DTT was used, its concentration was 10
mM.
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FOOTNOTES |
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Y.W. is a predoctoral fellow of the Howard Hughes Medical Institute (HHMI). W.W. P. is an associate and D.J.M. is an Investigator of the HHMI. This work was supported by HHMI (D.J.M.), the Robert A. Welch Foundation (D.J.M.), and the NIH (SPORE on Lung Cancer, D.J.M.), as well as grants to Dartmouth Medical School from the NIH (R01 CA-78814) and the National Foundation for Cancer Research. M.B.S. is an Oscar M. Cohn Professor.
1 These authors contributed equally to this work. 
Received for publication March 3, 2000. Revision received June 26, 2000. Accepted for publication July 20, 2000.
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M. Konopleva, E. Elstner, T. J. McQueen, T. Tsao, A. Sudarikov, W. Hu, W. D. Schober, R.-Y. Wang, D. Chism, S. M. Kornblau, et al. Peroxisome proliferator-activated receptor {gamma} and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias Mol. Cancer Ther., October 1, 2004; 3(10): 1249 - 1262. [Abstract] [Full Text] [PDF]
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),
CDDO (
), or CDDO-Me (
). CDDO-Me was toxic to COS-1 cells at 1
µM, so the highest dose used was 0.3 µM.
B, Effects of different doses of the same ligands on
NCoR/PPAR