Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium Cancer Health Disparities Conference 2009
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hisatake, J.-i.
Right arrow Articles by Koeffler, H. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hisatake, J.-i.
Right arrow Articles by Koeffler, H. P.
[Cancer Research 60, 5494-5498, October 1, 2000]
© 2000 American Association for Cancer Research

Experimental Therapeutics

Down-Regulation of Prostate-specific Antigen Expression by Ligands for Peroxisome Proliferator-activated Receptor {gamma} in Human Prostate Cancer1

Jun-ichi Hisatake2, Takeyuki Ikezoe, Michael Carey, Stuart Holden, Shigeru Tomoyasu and H. Phillip Koeffler

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.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The peroxisome proliferator-activated receptor gamma (PPAR{gamma}) is a member of the nuclear receptor superfamily. Recent studies found that ligand-activated PPAR{gamma} regulated differentiation and clonal growth of several types of cancer cells, including prostate cancer, suggesting that PPAR{gamma} could be a tumor suppressor. Troglitazone was a widely used antidiabetic drug that activates PPAR{gamma}. 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{gamma} ligands troglitazone (10-5 M), pioglitazone (10-5 M), or 15-deoxy-{Delta}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{gamma} 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
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the United States, prostate cancer is the most common male-related malignancy. It usually begins as an androgen-dependent tumor that responds to blockade of androgen stimulation by either pharmacological or surgical strategies. However, subsequent relapse occurs and the disease often reemerges within a few years in a poorly differentiated, androgen-independent form. Although androgen independent, most of these tumors continue to express ARs3 and androgen-responsive genes, such as PSA (1) . Because PSA is produced almost exclusively by the prostate epithelial cells, it has been used as a serum marker for diagnosis and progression of prostate cancer (2) . The 5' upstream promoter and enhancer region of the PSA gene has been extensively analyzed. Previous studies have identified several AREs in this region and have shown that expression of PSA is regulated by binding of the androgen/AR complex to AREs (3, 4, 5, 6, 7) .

The PPAR{gamma} is a member of the nuclear hormone receptor superfamily, which includes receptors for vitamin D, retinoic acid, thyroid hormone, and glucocorticoids. PPAR{gamma} 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{gamma} (10 , 11) . Recent studies have shown that ligand activation of PPAR{gamma} 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{gamma} mutations occur in colon cancer cells from a subset of patients (18) . These observations suggest that PPAR{gamma} could behave as a tumor suppressor and ligands for PPAR{gamma} 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{gamma} ligands might be controlling the reemergence of the disease and showed that they were able to depress activation of androgen-responsive genes.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient.
A 75-year-old man with prostate cancer (adenocarcinoma, Gleason score VII) had a radical prostatectomy performed in June 1993. There was no involvement of either the seminal vesicles or pelvic or abdominal lymph nodes. The individual was followed closely with serial serum PSA determinations, and these levels remained undetectable. However, in April 1997 his serum PSA jumped to 2.97 ng/ml, and by October 1997, it rose to 4.58 ng/ml. He had no other evidence of metastasis as assessed by biopsy of tumor bed, analysis of bone marrow aspirate and biopsy, and a bone scan. Due to the detectable levels of serum PSA, the patient had a diagnosis of occult recurrence.

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{gamma} 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{gamma} antibody (Calbiochem, San Diego, CA). The blots were developed using the enhanced chemiluminescence kit (Amersham Corp.).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Data.
The patient had a radical prostatectomy for Gleason score VII prostate cancer in July 1993. In April 1997, his serum PSA began to rise at a rate of 0.3 ng/ml per month. In June 1998, he had CAT scans of the pelvis and a bone survey; no metastatic disease was detectable. With his serum PSA in the range of 7 ng/ml, he was begun on oral troglitazone. Over the subsequent 14 months, he has continued on troglitazone and his PSA has remained in a range of about 6.5–7.5 ng/ml (Fig. 1)Citation . 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.



View larger version (11K):
[in this window]
[in a new window]
  		Fig. 1. Serum PSA levels obtained from an individual after prostatectomy for prostate cancer. Open arrowhead, starting point of troglitazone (600 mg/day); closed arrowhead, the point that the dose of troglitazone (800 mg) was increased.

 
Antiandrogen Effect of Troglitazone Using a Variety of PSA Promoter/Enhancer Reporter Constructs.
To explore potential mechanisms by which PPAR{gamma} 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)Citation . In addition, PGZ (10-5 M), a new TZD derivative, as well as 15dPGJ2 (10-5 M), a natural ligand for PPAR{gamma}, 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{gamma} 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)Citation . 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)Citation .



View larger version (16K):
[in this window]
[in a new window]
  		Fig. 2. Effect of PPAR{gamma} ligands on transcriptional activity of PSA promoter/enhancer in LNCaP cells. The reporter construct (PSA P/E-Luc) is shown at the top. LNCaP cells were transfected with PSA P/E-Luc (5.0 µg). DHT (10-9 M) either with or without 10-5 M PPAR{gamma} ligand was added. PSV-ß-galactosidase vector was cotransfected for normalization. SDs from three or more repetitions of the experiment are shown. *, P <= 0.05 as determined by Student’s t test difference compared with DHT alone. Trgz, troglitazone.

 


View larger version (20K):
[in this window]
[in a new window]
  		Fig. 3. Effect of troglitazone on either wild-type or mutant PSA enhancer. The reporter constructs (PSA enhancer E4-LUC and PSA enhancer E4 S-All-LUC) are shown at the top. Wild-type and mutant ARE sites are represented by boxes and crosses, respectively. LNCaP cells were transfected with the reporter construct (5.0 µg), and DHT was added to a final concentration of 10-9 M either with or without 10-5 M troglitazone (Trgz). PSV-ß-galactosidase vector was cotransfected for normalization. SDs from three or more repetitions of the experiment are shown. *, P <= 0.05 as determined by Student’s t test difference compared with DHT alone.

 
Additional studies used the PSA ARE I concatmerized and fused to a luciferase reporter construct (ARE4-E4Lux). LNCaP cells were transfected with ARE4-E4Lux and cultured with different amounts of DHT either with or without troglitazone (10-5 M; Fig. 4Citation ). 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.



View larger version (16K):
[in this window]
[in a new window]
  		Fig. 4. Effect of troglitazone on ARE activation in LNCaP cells. The reporter construct (ARE4-E4Lux) is shown at the top. LNCaP cells were transfected with ARE4-E4Lux (5.0 µg). Different concentrations of DHT (10-9, 10-8, and 10-7 M) were added either with or without troglitazone (10-5 M). PSV-ß-galactosidase vector was cotransfected for normalization. SDs from three or more repetitions of the experiment are shown. *, P <= 0.05 as determined by Student’s t test difference compared with DHT alone.

 
Effect of Troglitazone on PSA, AR, and PPAR{gamma} Protein Expression.
Cytoplasmic PSA protein expression was studied by Western blot analyses of LNCaP cells cultured with or without troglitazone and DHT for different durations (Fig. 5)Citation . 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{gamma} (Fig. 5)Citation .



View larger version (46K):
[in this window]
[in a new window]
  		Fig. 5. Western blot analysis of PSA, AR, PPAR{gamma}, and actin in LNCaP cells treated with troglitazone. Cells were incubated in medium with 10% charcoal-striped FBS for 24 h before the addition of 10-9 M DHT either with (+) or without (-) 10-5 M troglitazone (Trgz). After the addition of reagents, cells were incubated for 12 h and 1, 2, and 3 days. Control: cell lysates harvested before the addition of reagents. The band intensity was measured using a densitometer.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Novel therapies for the treatment of prostate cancer are needed. Previously, we showed that troglitazone could inhibit the growth of human prostate cancer cells both in vitro as well as when proliferating as xenografts in triple immunodeficient mice (12) . Because of these experiments as well as studies done by colleagues in Boston (22 , 23) , we initiated a trial of troglitazone in an individual who had developed a detectable serum PSA several years after prostatectomy with curative intent. Before starting troglitazone, the patient had increasing PSA levels over nearly a 2-year duration. The patient was begun on 600–800 mg/day of troglitazone p.o. He had no toxicities from the administration of the troglitazone; his liver function studies were all in the normal range.

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{gamma} 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 {kappa}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{gamma} 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)Citation . 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{gamma} (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{gamma} (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{gamma}; 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{gamma} ligand in the treatment of low-burden prostate cancer.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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. Back

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. Back

3 The abbreviations used are: AR, androgen receptor; PSA, prostate-specific antigen; PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}; DHT, dihydrotestosterone; ARE, AR response element; 15dPGJ2, 15-deoxy-{Delta}12,14-prostaglandin J2; FBS, fetal bovine serum; CAT, computerized axial tomography; TZD, thiazolidinedione; PGZ, pioglitazone. Back

Received 12/28/99. Accepted 8/ 4/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Prins G. S., Sklarew R. J., Pertschuk L. P. Image analysis of androgen receptor immunostaining in prostate cancer accurately predicts response to hormonal therapy. J. Urol., 159: 641-649, 1998.[Medline]
  2. Polascik T. J., Oesterling J. E., Partin A. W. Prostate specific antigen: a decade of discovery—what we have learned and where we are going. J. Urol., 162: 293-306, 1999.[Medline]
  3. Pang S., Dannull J., Kaboo R., Xie Y., Tso C. L., Michel K., deKernion J. B., Belldegrun A. S. Identification of a positive regulatory element responsible for tissue-specific expression of prostate-specific antigen. Cancer Res., 57: 495-499, 1997.[Abstract/Free Full Text]
  4. Zhang S., Murtha P. E., Young C. Y. Defining a functional androgen responsive element in the 5' far upstream flanking region of the prostate-specific antigen gene. Biochem. Biophys. Res. Commun., 231: 784-788, 1997.[Medline]
  5. Schuur E. R., Henderson G. A., Kmetec L. A., Miller J. D., Lamparski H. G., Henderson D. R. Prostate-specific antigen expression is regulated by an upstream enhancer. J. Biol. Chem., 271: 7043-7051, 1996.[Abstract/Free Full Text]
  6. Cleutjens K. B., van Eekelen C. C., van der Korput H. A., Brinkmann A. O., Trapman J. Two androgen response regions cooperate in steroid hormone regulated activity of the prostate-specific antigen promoter. J. Biol. Chem., 271: 6379-6388, 1996.[Abstract/Free Full Text]
  7. Huang W., Shostak Y., Tarr P., Sawyers C., Carey M. Cooperative assembly of androgen receptor into a nucleoprotein complex that regulates the prostate-specific antigen enhancer. J. Biol. Chem., 274: 25756-25768, 1999.[Abstract/Free Full Text]
  8. Chawla A., Schwarz E. J., Dimaculangan D. D., Lazar M. A. Peroxisome proliferator-activated receptor (PPAR) {gamma}: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology, 135: 798-800, 1994.[Abstract]
  9. Kliewer S. A., Lehmann J. M., Willson T. M. Orphan nuclear receptors: shifting endocrinology into reverse. Science (Washington DC), 284: 757-760, 1999.[Abstract/Free Full Text]
  10. Forman B. M., Tontonoz P., Chen J., Brun R. P., Spiegelman B. M., Evans R. M. 15-Deoxy-{Delta} 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR {gamma}. Cell, 83: 803-812, 1995.[Medline]
  11. Lehmann J. M., Moore L. B., Smith-Oliver T. A., Wilkison W. O., Willson T. M., Kliewer S. A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor {gamma} (PPAR {gamma}). J. Biol. Chem., 270: 12953-12956, 1995.[Abstract/Free Full Text]
  12. Kubota T., Koshizuka K., Williamson E. A., Asou H., Said J. W., Holden S., Miyoshi I., Koeffler H. P. Ligand for peroxisome proliferator-activated receptor {gamma} (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res., 58: 3344-3352, 1998.[Abstract/Free Full Text]
  13. Mueller E., Sarraf P., Tontonoz P., Evans R. M., Martin K. J., Zhang M., Fletcher C., Singer S., Spiegelman B. M. Terminal differentiation of human breast cancer through PPAR {gamma}. Mol. Cell, 1: 465-470, 1998.[Medline]
  14. Elstner E., Muller C., Koshizuka K., Williamson E. A., Park D., Asou H., Shintaku P., Said J. W., Heber D., Koeffler H. P. Ligands for peroxisome proliferator-activated receptor {gamma} and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc. Natl. Acad. Sci. USA, 95: 8806-8811, 1998.[Abstract/Free Full Text]
  15. Sarraf P., Mueller E., Jones D., King F. J., DeAngelo D. J., Partridge J. B., Holden S. A., Chen L. B., Singer S., Fletcher C., Spiegelman B. M. Differentiation and reversal of malignant changes in colon cancer through PPAR {gamma}. Nat. Med., 4: 1046-1052, 1998.[Medline]
  16. Takahashi N., Okumura T., Motomura W., Fujimoto Y., Kawabata I., Kohgo Y. Activation of PPAR {gamma} inhibits cell growth and induces apoptosis in human gastric cancer cells. FEBS Lett., 455: 135-139, 1999.[Medline]
  17. Tontonoz P., Singer S., Forman B. M., Sarraf P., Fletcher J. A., Fletcher C. D., Brun R. P., Mueller E., Altiok S., Oppenheim H., Evans R. M., Spiegelman B. M. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor {gamma} and the retinoid X receptor. Proc. Natl. Acad. Sci. USA, 94: 237-241, 1997.[Abstract/Free Full Text]
  18. Sarraf P., Mueller E., Smith W. M., Wright H. M., Kum J. B., Aaltonen L. A., de la Chapelle A., Spiegelman B. M., Eng C. Loss-of-function mutations in PPAR {gamma} associated with human colon cancer. Mol. Cell, 3: 799-804, 1999.[Medline]
  19. Abreu-Martin M. T., Chari A., Palladino A. A., Craft N. A., Sawyers C. L. Mitogen-activated protein kinase kinase kinase 1 activates androgen receptor-dependent transcription and apoptosis in prostate cancer. Mol. Cell. Biol., 19: 5143-5154, 1999.[Abstract/Free Full Text]
  20. Watkins P. B., Whitcomb R. W. Hepatic dysfunction associated with troglitazone (Letter; comment). N. Engl. J. Med., 338: 916-917, 1998.[Free Full Text]
  21. Pang S., Taneja S., Dardashti K., Cohan P., Kaboo R., Sokoloff M., Tso C. L., Dekernion J. B., Belldegrun A. S. Prostate tissue specificity of the prostate-specific antigen promoter isolated from a patient with prostate cancer. Hum. Gene Ther., 6: 1417-1426, 1995.[Medline]
  22. Spiegelman, B. M. Differentiation of human tumors through ligand activation of PPAR {gamma}. 8th International Conference on Differentiation Therapy, Montreal, Canada, 1999, p. 34.
  23. Mueller, E., Sarraf, P., Smith, M., Kantoff, P., and Spiegelman, B. M. Differentiation therapy of human solid tumors via activation of PPAR {gamma}. 8th International Conference on Differentiation Therapy, Montreal, Canada, 1999, p. 38.
  24. Carter H. B., Pearson J. D., Metter E. J., Brant L. J., Chan D. W., Andres R., Fozard J. L., Walsh P. C. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. J. Am. Med. Assoc., 267: 2215-2220, 1992.[Abstract]
  25. Ricote M., Li A. C., Willson T. M., Kelly C. J., Glass C. K. The peroxisome proliferator-activated receptor-{gamma} is a negative regulator of macrophage activation. Nature (Lond.), 391: 79-82, 1998.[Medline]
  26. Jiang C., Ting A. T., Seed B. PPAR-{gamma} agonists inhibit production of monocyte inflammatory cytokines. Nature (Lond.), 391: 82-86, 1998.[Medline]
  27. Delerive P., Martin-Nizard F., Chinetti G., Trottein F., Fruchart J. C., Najib J., Duriez P., Staels B. Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ. Res., 85: 394-402, 1999.[Abstract/Free Full Text]
  28. Torchia J., Glass C., Rosenfeld M. G. Co-activators and co-repressors in the integration of transcriptional responses. Curr. Opin. Cell Biol., 10: 373-383, 1998.[Medline]
  29. Ledwith B. J., Manam S., Troilo P., Joslyn D. J., Galloway S. M., Nichols W. W. Activation of immediate-early gene expression by peroxisome proliferators in vitro. Mol. Carcinog., 8: 20-27, 1993.[Medline]
  30. Ledwith B. J., Johnson T. E., Wagner L. K., Pauley C. J., Manam S., Galloway S. M., Nichols W. W. Growth regulation by peroxisome proliferators: opposing activities in early and late G1. Cancer Res., 56: 3257-3264, 1996.[Abstract/Free Full Text]
  31. Sato N., Sadar M. D., Bruchovsky N., Saatcioglu F., Rennie P. S., Sato S., Lange P. H., Gleave M. E. Androgenic induction of prostate-specific antigen gene is repressed by protein-protein interaction between the androgen receptor and AP-1/c- Jun in the human prostate cancer cell line LNCaP. J. Biol. Chem., 272: 17485-17494, 1997.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 JCOHome page
R. Govindarajan, L. Ratnasinghe, D. L. Simmons, E. R. Siegel, M. V. Midathada, L. Kim, P. J. Kim, R. J. Owens, and N. P. Lang
Thiazolidinediones and the Risk of Lung, Prostate, and Colon Cancer in Patients With Diabetes
J. Clin. Oncol., April 20, 2007; 25(12): 1476 - 1481.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C.-C. Yang, Y.-C. Wang, S. Wei, L.-F. Lin, C.-S. Chen, C.-C. Lee, C.-C. Lin, and C.-S. Chen
Peroxisome Proliferator-Activated Receptor {gamma}-Independent Suppression of Androgen Receptor Expression by Troglitazone Mechanism and Pharmacologic Exploitation
Cancer Res., April 1, 2007; 67(7): 3229 - 3238.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
G. Kristiansen, J. Jacob, A.-C. Buckendahl, R. Grutzmann, I. Alldinger, B. Sipos, G. Kloppel, M. Bahra, J. M. Langrehr, P. Neuhaus, et al.
Peroxisome Proliferator-Activated Receptor {gamma} Is Highly Expressed in Pancreatic Cancer and Is Associated With Shorter Overall Survival Times.
Clin. Cancer Res., November 1, 2006; 12(21): 6444 - 6451.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
J.-S. Annicotte, I. Iankova, S. Miard, V. Fritz, D. Sarruf, A. Abella, M.-L. Berthe, D. Noel, A. Pillon, F. Iborra, et al.
Peroxisome Proliferator-Activated Receptor {gamma} Regulates E-Cadherin Expression and Inhibits Growth and Invasion of Prostate Cancer.
Mol. Cell. Biol., October 1, 2006; 26(20): 7561 - 7574.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
J-R Weng, C-Y Chen, J J Pinzone, M D Ringel, and C-S Chen
Beyond peroxisome proliferator-activated receptor {gamma} signaling: the multi-facets of the antitumor effect of thiazolidinediones.
Endocr. Relat. Cancer, June 1, 2006; 13(2): 401 - 413.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
C.-C. Yang, C.-Y. Ku, S. Wei, C.-W. Shiau, C.-S. Chen, J. J. Pinzone, M. D. Ringel, and C.-S. Chen
Peroxisome Proliferator-Activated Receptor {gamma}-Independent Repression of Prostate-Specific Antigen Expression by Thiazolidinediones in Prostate Cancer Cells
Mol. Pharmacol., May 1, 2006; 69(5): 1564 - 1570.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
A. Mori, S. Lehmann, J. O'Kelly, T. Kumagai, J. C. Desmond, M. Pervan, W. H. McBride, M. Kizaki, and H. P. Koeffler
Capsaicin, a Component of Red Peppers, Inhibits the Growth of Androgen-Independent, p53 Mutant Prostate Cancer Cells.
Cancer Res., March 15, 2006; 66(6): 3222 - 3229.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
K-M Fung, E N S Samara, C Wong, A Metwalli, R Krlin, B Bane, C Z Liu, J T Yang, J V Pitha, D J Culkin, et al.
Increased expression of type 2 3{alpha}-hydroxysteroid dehydrogenase/type 5 17{beta}-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma.
Endocr. Relat. Cancer, March 1, 2006; 13(1): 169 - 180.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
M. A. Murtaugh, K.-n. Ma, B. J. Caan, C. Sweeney, R. Wolff, W. S. Samowitz, J. D. Potter, and M. L. Slattery
Interactions of Peroxisome Proliferator-Activated Receptor {gamma} and Diet in Etiology of Colorectal Cancer
Cancer Epidemiol. Biomarkers Prev., May 1, 2005; 14(5): 1224 - 1229.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
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]

Home page
 Am. J. Clin. Nutr.Home page
S. C Larsson, M. Kumlin, M. Ingelman-Sundberg, and A. Wolk
Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms
Am. J. Clinical Nutrition, June 1, 2004; 79(6): 935 - 945.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
N. Strakova, J. Ehrmann, P. Dzubak, J. Bouchal, and Z. Kolar
The Synthetic Ligand of Peroxisome Proliferator-Activated Receptor-{gamma} Ciglitazone Affects Human Glioblastoma Cell Lines
J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1239 - 1247.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
T. Kumagai, T. Ikezoe, D. Gui, J. O'Kelly, X.-J. Tong, F. J. Cohen, J. W. Said, and H. P. Koeffler
RWJ-241947 (MCC-555), A Unique Peroxisome Proliferator-Activated Receptor-{gamma} Ligand with Antitumor Activity against Human Prostate Cancer in Vitro and in Beige/Nude/ X-Linked Immunodeficient Mice and Enhancement of Apoptosis in Myeloma Cells Induced by Arsenic Trioxide
Clin. Cancer Res., February 15, 2004; 10(4): 1508 - 1520.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. C. Desmond, J. C. Mountford, M. T. Drayson, E. A. Walker, M. Hewison, J. P. Ride, Q. T. Luong, R. E. Hayden, E. F. Vanin, and C. M. Bunce
The Aldo-Keto Reductase AKR1C3 Is a Novel Suppressor of Cell Differentiation That Provides a Plausible Target for the Non-Cyclooxygenase-dependent Antineoplastic Actions of Nonsteroidal Anti-Inflammatory Drugs
Cancer Res., January 15, 2003; 63(2): 505 - 512.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
H. P. Koeffler
Peroxisome Proliferator-activated Receptor {gamma} and Cancers
Clin. Cancer Res., January 1, 2003; 9(1): 1 - 9.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
J. Auwerx
Nuclear Receptors: I. PPARgamma in the gastrointestinal tract: gain or pain?
Am J Physiol Gastrointest Liver Physiol, April 1, 2002; 282(4): G581 - G585.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
L. Kopelovich, J. R. Fay, R. I. Glazer, and J. A. Crowell
Peroxisome Proliferator-activated Receptor Modulators As Potential Chemopreventive Agents
Mol. Cancer Ther., March 1, 2002; 1(5): 357 - 363.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
D. J. A. Adamson, D. Frew, R. Tatoud, C. R. Wolf, and C. N. A. Palmer
Diclofenac Antagonizes Peroxisome Proliferator-Activated Receptor-gamma Signaling
Mol. Pharmacol., January 1, 2002; 61(1): 7 - 12.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hisatake, J.-i.
Right arrow Articles by Koeffler, H. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hisatake, J.-i.
Right arrow Articles by Koeffler, H. P.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online