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Experimental Therapeutics |
in Human Prostate Cancer1
Division of Hematology/Oncology [J-i. H., T. I., H. P. K.] and Department of Surgery [S. H.], Cedars-Sinai Medical Center, University of California–Los Angeles School of Medicine, Los Angeles, California 90048; Biological Chemistry and Molecular Biology Institute, University of California, Los Angeles, California 90095 [M. C.]; and Department of Hematology, Showa University School of Medicine, Tokyo 142, Japan [S. T.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) is a
member of the nuclear receptor superfamily. Recent studies found that
ligand-activated PPAR regulated differentiation and clonal growth of
several types of cancer cells, including prostate cancer, suggesting
that PPAR could be a tumor suppressor. Troglitazone was a widely
used antidiabetic drug that activates PPAR. Recently, we reported
that this agent had antiprostate cancer effects in vitro
and in vivo. In this study, we administered troglitazone
for over 1.5 years to an individual with occult recurrent prostate
cancer. Using the prostate-specific antigen (PSA) levels as a surrogate
marker of the disease, the oral administration of troglitazone
(600–800 mg/day) reduced the increase velocity of PSA levels,
suggesting clinical efficacy of troglitazone in prostate cancer. PSA
promoter/enhancer reporter assays showed that the PPAR ligands
troglitazone (10-5 M), pioglitazone (10-5 M),
or 15-deoxy-
12,14-prostaglandin J2 (10-5 M)
down-regulated androgen-stimulated reporter gene activity in LNCaP
cells, a prostate cancer cell line. The PSA promoter contains androgen
receptor response elements (AREs). Reporter gene studies showed that
troglitazone inhibited androgen activation of the AREs in the PSA
regulatory region. Consistent with inhibition of gene expression, 2
days of incubation of LNCaP with troglitazone dramatically suppressed
PSA protein expression without suppressing AR expression, suggesting
that troglitazone inhibited ARE activation by a mechanism other than
down-regulation of expression of the AR. Taken together, ligands of
PPAR may be a useful therapeutic approach for the treatment of
prostate cancer and may be acting, in part, by inhibiting
transactivation of androgen-responsive genes. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The PPAR is a member of the nuclear hormone receptor superfamily,
which includes receptors for vitamin D, retinoic acid, thyroid hormone,
and glucocorticoids. PPAR is highly expressed in fat cells, and the
receptor is important in inducing differentiation of preadipocytes to
adipocytes (8)
. The receptor requires ligand activation.
Several ligands have been identified, including the synthetic
antidiabetic TZD drugs, nonsteroidal anti-inflammatory agents, and
natural ligands such as 15dPGJ2 (9)
.
Troglitazone is a TZD that was widely used for insulin-resistant
diabetes mellitus; it has been identified as a specific ligand for
PPAR (10
, 11)
. Recent studies have shown that ligand
activation of PPAR can induce differentiation and inhibit
proliferation of prostate (12)
, breast (13
, 14)
, colon (15)
, and gastric cancer cells
(16)
, as well as liposarcomas (17)
in
vitro and in vivo. Moreover, somatic PPAR mutations
occur in colon cancer cells from a subset of patients
(18)
. These observations suggest that PPAR could behave
as a tumor suppressor and ligands for PPAR might be useful for
cancer therapy. In the present study, we evaluated the effect of
administration of troglitazone for over 1.5 years to an individual who
had an increasing serum PSA after radical prostatectomy with curative
intent. Furthermore, we analyzed how PPAR ligands might be
controlling the reemergence of the disease and showed that they were
able to depress activation of androgen-responsive genes.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In June 1998, after informed consent, the patient was begun on troglitazone initially at the dose of 600 mg but shortly increased to 800 mg p.o. once daily. The serum PSA levels, blood counts, and clinical chemistry including liver function studies were measured once or twice a month. After 1.5 years of treatment, he was analyzed for metastatic disease by pelvic and abdominal CAT scans and whole-body bone scans, as well as plain films of the chest. None of these have shown abnormalities.
Cells and Compounds.
LNCaP cells were obtained from American Type Culture Collection
(Manassas, VA). These cells were maintained in RPMI 1640 with
10% FBS. Troglitazone (Parke-Davis/Warner-Lambert), PGZ (Takeda
Chemical Industries, Ltd., Tokyo, Japan), and
15dPGJ2 (Calbiochem, La Jolla, CA) were dissolved
in a solution containing 50% DMSO and 50% ethanol. DHT (Sigma
Chemical Co., St. Louis, MO) was dissolved in 100% ethanol. For all
compounds, the diluent was never present at 
0.1% in the experiments
and control dishes with this concentration of diluent had no detectable
effect.
Plasmids.
A 564-bp fragment of the PSA promoter with a 2.4-kb enhancer sequence
(-5322 to -2925) cloned upstream of luciferase (PSA P/E-Luc) was used
(3
, 19)
. Also, ARE4-E4Lux, which is the multimerized four
consensus AREs from the PSA promoter cloned upstream of the luciferase
gene in the pGL3 vector (Promega, Chicago, IL) was used. The PSA
enhancer (wild type)-E4LUC and the PSA enhancer (S-All)-E4LUC, which
contains four mutated AREs, were also studied (7)
.
Transfections and Luciferase Assay.
LNCaP cells were incubated in RPMI 1640 with 10% FBS until 50–70%
confluency. Cells were transfected with the indicated plasmids using
the Superfect (Qiagen, Santa Clarita, CA) under serum-free conditions.
A PSV-ß-galactosidase vector was included as an internal control for
efficiency of transfections. Following transfections, cells were
incubated with 10% charcoal-stripped FBS RPMI 1640 either with or
without 10-9 M DHT and either with or without
ligands for PPAR for 72 h. Cells were collected with tissue
lysis buffer (Promega). Luciferase activity of the cell lysates was
measured by luminometry, and activities were normalized by
ß-galactosidase activities. All transfection experiments were carried
out in triplicate wells and repeated separately at least three times.
Western Blot Analyses.
LNCaP cells were incubated in RPMI 1640 containing 10% charcoal
dextran-treated FBS for 24 h before the addition of
10-9 M DHT with or without
10-5 M troglitazone. After incubation, cells
were washed twice in PBS, suspended in lysis buffer [50 mM
Tris (pH 8.0), 150 mM NaCl, 0.1% SDS, 0.5% sodium
deoxycholate, 1% NP40, 100 µg/ml phenylmethylsulfonyl fluoride, 2
µg/ml aprotinin, 1 µg/ml pepstatin, and 10 µg/ml leupeptin], and
placed on ice for 30 min. After centrifugation at 15,000 x g for 20 min at 4°C, the supernatant was
collected. Protein concentrations were quantitated using the Bio-Rad
assay (Bio-Rad Laboratories, Hercules, CA). Whole lysates (20 µg)
were resolved by 4–15% SDS polyacrylamide gel, transferred to an
immobilon polyvinylidene difuride membrane (Amersham Corp., Arlington
Heights, IL), and probed sequentially with anti-PSA (S.C. 7316),
anti-AR, antiactin antibodies (Santa Cruz Biotechnology Inc., Santa
Cruz, CA), and anti-PPAR antibody (Calbiochem, San Diego, CA). The
blots were developed using the enhanced chemiluminescence kit (Amersham
Corp.).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Recent repeat pelvic and abdominal CAT scans, bone scans, and bone
survey did not detect prostate cancer. Because rare cases of severe
liver dysfunction occur during troglitazone therapy in diabetic
patients (20)
, we closely monitored his liver functions as
well as performed routine blood chemistries. He had had no
abnormalities in these studies (data not shown). No side effects have
been observed. Nevertheless, because of potential liver toxicity, he
discontinued troglitazone and began daily Casadex (50 mg) and Proscar
(5 mg). His PSA fell to 2.8 ng/ml over the next several months of this
therapy, consistent with his prostate cancer being sensitive to
androgen ablation.
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ligands inhibited
levels of PSA, we analyzed the effect of troglitazone on the ability of
DHT to transactivate the PSA promoter/enhancer. The LNCaP prostate
cancer cells were cultured with DHT (10-9 M)
after they were transfected with the PSA promoter/enhancer-luciferase
reporter vector. The reporter activity increased about 17-fold as
compared with nontreated control LNCaP cells. This result was
consistent with previous observations (4
, 5
, 21)
. When
cells were treated with both troglitazone (10-5
M) and DHT (10-9 M), luciferase activity was
dramatically reduced by 60% compared with DHT alone (Fig. 2)
. In addition, PGZ (10-5 M), a new TZD derivative, as well
as 15dPGJ2 (10-5 M), a
natural ligand for PPAR, also decreased DHT-stimulated luciferase
activity by 66% and 70%, respectively. Exposure of LNCaP cells to
troglitazone, PGZ, or 15dPGJ2 alone reduced
luciferase activity by 70%, 70%, and 80%, respectively, compared
with nontreated control cells. These findings indicated that PPAR
ligands inhibited the ability of androgens to transactivate the PSA
promoter/enhancer. We also studied the effect of troglitazone using the
luciferase-reporter construct that contained a 496-bp fragment of the
PSA enhancer (Fig. 3A)
. As reported in a previous study (7)
, this
fragment contains multiple AREs. Luciferase activity was stimulated by
DHT (10-9 M), and troglitazone inhibited this
stimulation by 62%. As expected, DHT did not activate and troglitazone
did not inhibit luciferase activity when the four most active AREs were
mutated (Fig. 3B)
.
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). DHT increased ARE activity in a dose-dependent manner. Troglitazone
reduced DHT-stimulated ARE activity by about 60%, suggesting that the
inhibition of the PSA gene expression by troglitazone was
probably attributed to a reduction of ARE activity.
|
Protein Expression.
. LNCaP cells constitutively expressed PSA protein. When these cells
were incubated with 10-9 M DHT, PSA expression
increased about 2-fold by 12 h of culture. Troglitazone
(10-5 M) suppressed PSA expression induced by
DHT at each time point. For example, at day 3, troglitazone suppressed
PSA levels by 85% as compared with cells cultured with DHT alone.
Moreover, we examined levels of AR in LNCaP to determine whether
troglitazone suppressed PSA through inhibition of AR expression.
Troglitazone (10-5 M) did not significantly
affect levels of AR expression compared with LNCaP cells cultured with
DHT alone. Furthermore, neither DHT nor troglitazone affected levels of
PPAR (Fig. 5)
.
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|
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To evaluate the efficacy of troglitazone, the serum PSA velocity was calculated as described previously (24) . Before initiation of troglitazone, it was 1.6 ng/ml per year; on the other hand, after initiation of therapy, PSA velocity decreased to -0.17 ng/ml per year. The patient also has been examined repeatedly for metastatic disease. Most recently, on the 17th month of troglitazone therapy, pelvic and abdominal CAT scans, bone scans, skeletal series, and blood chemistries were normal.
The mechanism by which troglitazone inhibits prostate cancer cells was
further investigated. Previous studies have shown that PPAR ligand
is able to inhibit activation of a number of secondary signaling
pathways including Fos/Jun, signal transducer and activator of
transcription, and nuclear factor 
ß (25, 26, 27)
.
We hypothesized that perhaps troglitazone was inhibiting the activation
of the AR. Therefore, we examined in detail an androgen-responsive
gene, PSA. The PSA gene has eight or more AREs
that are upstream of the start site of transcription (7)
.
To examine the effect of troglitazone on the promoter/enhancer of the
PSA gene, a construct that contained the 5' upstream region
of the PSA gene with the eight AREs was fused to a reporter
gene (luciferase) and transfected into LNCaP cells. DHT markedly
enhanced transcriptional activity of the reporter, and troglitazone,
PGZ, and 15dPJ2 inhibited the DHT-mediated
transactivation. Mutation of the AREs resulted in loss of both
activation by DHT and inhibition by troglitazone. To determine whether
the inhibition mediated by troglitazone was at least, in part, through
the AREs, a concatamerized ARE from the PSA promoter region (ARE I;
Ref. 6
) was fused to the reporter gene and transiently
transfected into LNCaP cells. Again, troglitazone inhibited the
transactivation of DHT, providing evidence that troglitazone can
apparently have an antiandrogen effect.
Additional experiments explored whether the PPAR ligand could also
inhibit androgen-induced production of PSA. Exposure of LNCaP
cells simultaneously to DHT and troglitazone resulted in inhibition of
accumulation of PSA protein compared with exposure to DHT alone, as
shown by Western blotting (Fig. 4)
. Reprobing of the Western blot
showed that the down-regulation of PSA expression was not mediated
through down-regulation of AR. Because troglitazone is able to inhibit
transactivation of a number of secondary signaling pathways, it may be
either inhibiting coactivators or stimulating corepressors of the
activated AR. A recent report has shown that activated AR requires
coactivators for efficient expression of androgen-responsive genes
(28)
. Another less likely hypothesis results from studies
that have shown that induction of immediate early genes such as
c-Jun and c-Myc can be mediated by ligands of
PPAR (29
, 30)
and complexes of c-Jun and c-Fos can
disrupt transactivation of the ARs (31)
. Additional
studies are clearly required to elucidate the mechanism by which
thiazolidadiones mediate their antiandrogen activities.
The antiproliferative effects of troglitazone cannot totally be
explained by inhibition of the androgen signaling pathway. Prior
studies showed that the PC3 cells, which have a nonfunctional, mutated
AR, are inhibited in their proliferation in vitro and
in vivo by troglitazone and other ligands of PPAR
(12)
. In addition, studies by others as well as ourselves
have demonstrated that cancer cells from a variety of tissues including
colon, breast, fat, and stomach can be inhibited in their proliferation
by ligands of PPAR; and these cancers are not under androgen
control. This would be congruent with the hypothesis that
thiazolidiones are affecting key cofactors of activated signaling
pathways in these transformed cells.
In this study, we provide evidence that troglitazone can have an
antiandrogen effect as shown by the ability of this agent to inhibit
transactivation of PSA, a gene having multiple AREs. This
has led to the stabilization of the serum PSA in our patient for
greater than 17 months. The stabilization could merely reflect a direct
effect of troglitazone on PSA production. More likely, however,
troglitazone is having an antiproliferative action on the prostate
cancer cells, in part through inhibition of the AR pathway. The
experience reported here suggests that an expanded clinical study is
worthwhile to determine the efficacy of a PPAR ligand in the
treatment of low-burden prostate cancer.
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FOOTNOTES |
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1 Supported by United States Department of
Defense and NIH grants as well as the CaPCure Foundation, Parker Hughes
Trust, C. and H. Koeffler Fund, Horn Trust, and the Aron Eschman
Fund. 
2 To whom requests for reprints should be
addressed, at Cedars-Sinai Medical Center, Division of
Hematology/Oncology, 8700 Beverly Boulevard, B-215, Los Angeles, CA
90048. Phone: (310) 855-4609; Fax: (310) 659-9741.
3 The abbreviations used are: AR, androgen
receptor; PSA, prostate-specific antigen; PPAR, peroxisome
proliferator-activated receptor ; DHT, dihydrotestosterone; ARE, AR
response element; 15dPGJ2, 15-deoxy-12,14-prostaglandin
J2; FBS, fetal bovine serum; CAT, computerized axial
tomography; TZD, thiazolidinedione; PGZ, pioglitazone.
Received 12/28/99. Accepted 8/ 4/00.
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0.05 as determined by Student’s
t test difference compared with DHT alone.
Trgz, troglitazone.
