Molecular Cancer Therapeutics CTRC-AACR San Antonio Breast Cancer Symposium
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 Kopelovich, L.
Right arrow Articles by Crowell, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kopelovich, L.
Right arrow Articles by Crowell, J. A.
Vol. 1, 357-363, March 2002     Molecular Cancer Therapeutics
© 2002 American Association for Cancer Research

Minireviews

Peroxisome Proliferator-activated Receptor Modulators As Potential Chemopreventive Agents

Levy Kopelovich1, Judith R. Fay, Robert I. Glazer and James A. Crowell

National Cancer Institute, Division of Cancer Prevention, Bethesda, Maryland 20892-7322 [L. K., J. R. F., J. A. C.] Department of Pharmacology, Georgetown University School of Medicine, Washington, D.C. 20057 [R. I. G.]


   Abstract
Top
 Abstract
Introduction
 PPAR{gamma} and Cancer
 PPAR{alpha} and Cancer
 PPAR{delta} and Cancer
 PPAR Modulators
 Conclusions
 References
 
Peroxisome proliferator-activated receptors (PPARs), members of the superfamily of nuclear steroid hormone receptors, have traditionally been studied for their role in lipid, glucose, and energy homeostasis. Recent evidence suggests that pharmacological activation of PPAR{gamma} and PPAR{alpha}, and inhibition of PPAR{delta}, may prevent cancer. PPAR{gamma} agonists induce differentiation, inhibit the growth of established tumor cells in vitro and in vivo, and have chemopreventive effects in animal models. PPAR{alpha} has anti-inflammatory and differentiating activity and protects against the oxidative damage associated with aging. In contrast, PPAR{delta} expression may be a factor in colorectal carcinogenesis. PPAR{delta} is normally repressed by the adenomatous polyposis coli tumor suppressor gene, and impaired adenomatous polyposis coli is strongly associated with human colorectal cancer risk. This review presents a rationale for using PPAR modulators as cancer chemopreventive drugs.


   Introduction
Top
 Abstract
 Introduction
PPAR{gamma} and Cancer
 PPAR{alpha} and Cancer
 PPAR{delta} and Cancer
 PPAR Modulators
 Conclusions
 References
 
PPARs 2 are ligand-activated transcription factors that heterodimerize with the RXRs and bind to peroxisomal proliferator response elements in the promoter region of target genes. Three PPAR isoforms have been cloned ({alpha}, {gamma}, and {delta}), each exhibiting distinct patterns of tissue distribution and ligand specificity. PPAR{alpha} regulates numerous aspects of fatty acid catabolism, whereas PPAR{gamma} controls adipocyte differentiation, systemic glucose levels, and lipid homeostasis (reviewed in Refs. 1 and 2). PPAR{delta} is involved in development, embryo implantation, myelination of the corpus callosum, lipid metabolism, and epidermal cell proliferation (3, 4). Significant species differences in response to PPAR{alpha}, but not PPAR{gamma}, have been noted. Specifically relevant to cancer, PPAR{alpha} agonists increase peroxisomes and induce hepatomegaly and liver cancer in rodents. However, humans are refractory to the hepatotoxic actions of these drugs (reviewed in Ref. 5). In the following sections, evidence is presented for each PPAR class and the specific PPAR agonists that may play a role in cancer chemoprevention.


   PPAR{gamma} and Cancer
Top
 Abstract
 Introduction
 PPAR{gamma} and Cancer
PPAR{alpha} and Cancer
 PPAR{delta} and Cancer
 PPAR Modulators
 Conclusions
 References
 
The observation that PPAR{gamma} stimulates adipose differentiation in cultured mouse fibroblasts generated interest in the receptor’s potential anticancer effects (6). Subsequent studies showed that activation of the receptor inhibits proliferation, and in some cases induces differentiation and/or apoptosis, in a variety of tumor cell lines (Table 1). Some of the most extensive work has been conducted in the colon, where PPAR{gamma} is expressed at high levels in normal tissue (7), and in both well- and poorly differentiated colon cancers (8). PPAR{gamma}-selective ligands inhibit proliferation and induce differentiation in colon cancer cell lines (8, 9) and diminish growth of human colon tumor xenografts (Ref. 8; Table 2). Importantly, for the purposes of chemoprevention, these ligands prevent the development of carcinogen-induced preneoplastic aberrant crypt foci in rats (10). Loss-of-function somatic mutations in the PPAR{gamma} gene are found in sporadic human colon cancers, suggesting that PPAR{gamma} may function directly as a tumor suppressor (11). PPAR{gamma} agonists also suppress macrophage activation and inflammatory cytokine production in vitro (12, 13) and reduce inflammation (10, 14) and neoplastic lesion development (10) in rodent models of inflammatory bowel disease. The latter finding is particularly relevant to chemoprevention, because the risk of colorectal cancer is increased in patients with this disease (reviewed in Ref. 15).


View this table:
[in this window]
[in a new window]

  		Table 1 Antiproliferative effects of PPAR{gamma} ligands in vitroa

 

View this table:
[in this window]
[in a new window]

  		Table 2 Anticancer effects of PPAR{gamma} ligands in animal studiesa

 
In contrast, other studies indicate that PPAR{gamma} activation promotes colon cancer in mice carrying a nonsense mutation in the APC tumor suppressor gene; defective APC is highly associated with human colorectal cancer risk (16). The TZDs troglitazone and rosiglitazone enhance colon tumorigenicity in these genetically predisposed mice; the more potent PPAR{gamma} agonist rosiglitazone induces more malignant tumors. However, pharmacological doses of troglitazone are not tumorigenic in wild-type mice, suggesting that increased risk is limited to animals harboring a mutant APC gene (17, 18).

Data available from other target sites suggest that PPAR{gamma} activation has chemopreventive potential. The receptor is expressed in human breast cancer cell lines and breast adenocarcinomas, and TZDs inhibit growth of breast cancer cells in vitro and in vivo, inducing differentiation in some cases (19, 20). However, cell lines expressing the highest levels of PPAR{gamma} are relatively unresponsive to TZD treatment. Adding a mitogen-activated protein kinase inhibitor overcomes this insensitivity, suggesting that phosphorylation prevents PPAR{gamma} activation (19).

The relevance of PPAR{gamma} activation for chemoprevention has been demonstrated in rodent mammary cancer models. The highly potent and specific PPAR{gamma} ligand GW 7845 significantly reduces tumor incidence, number, and weight in estrogen receptor-positive mammary tumors when fed to rats after carcinogen administration. Additive effects are observed on coadministration with suboptimal doses of the antiestrogen tamoxifen (21). Likewise, troglitazone prevents development of carcinogen-induced early neoplastic lesions in mouse mammary gland organ culture when administered during initiation or promotion stages. Synergism was noted with RXR-selective ligands (22), although similar effects were not observed in human breast cancer cell lines induced to differentiate in response to PPAR{gamma} activation (19). PPAR{gamma} ligands also diminish expression of aromatase (23), the rate-limiting enzyme in estrogen biosynthesis, which may contribute to chemopreventive effects in estrogen-responsive tissues.

In the prostate, PPAR{gamma} is expressed in primary cancers and cell lines, and receptor agonists display antiproliferative effects in vitro (24–26) and in xenografts in nude mice (24); effects in vivo are associated with necrotic, as well as apoptotic changes (24). Additionally, a subset of human prostate tumors carry hemizygous deletions of the PPAR{gamma} gene (25). In preliminary clinical studies, 20% (8 of 41) of prostate cancer patients treated with troglitazone showed decreased serum prostate-specific antigen levels, and 39% showed prolonged stabilization (25). Consistent with these findings, troglitazone decreases prostate-specific antigen levels in prostate cancer cell lines (24, 25). The actions of PPAR{gamma} ligands in the prostate may be associated with decreased activation of the androgen receptor (27) or a reduction in circulating estrogens (reviewed in Ref. 28), secondary to reduced aromatase expression (23).

PPAR{gamma} ligands also inhibit proliferation of human lung, urinary bladder, pancreatic, neuroblastoma, gastric, and liposarcoma cell lines (Table 1) and induce differentiation and inhibit growth of liposarcomas in patients (29). The activated form of matrix metalloproteinase-2, strongly associated with tumor growth, metastasis, and angiogenesis (30), markedly decreases in lung cancer cells treated with PPAR{gamma} agonists (31). Furthermore, PPAR{gamma} activators are direct inhibitors of angiogenesis both in vitro and in vivo (32, 33). A role for PPAR{gamma} in thyroid follicular carcinoma is suggested by the presence in these tumors of a PAX8-PPAR{gamma}1 fusion oncoprotein, which functions as a dominant negative suppressor of wild-type PPAR{gamma} (34).

Recent investigations have provided clues about the signaling pathways used by PPAR{gamma} agonists to suppress neoplasia. Inhibition of tumor cell growth has been associated with G1 cell cycle arrest (9, 35, 36), which in some cases is linked to loss of DNA binding activity of the transcriptional regulator E2F/DP (37). Other mechanisms that may be involved include upregulation of the cyclin-dependent kinase inhibitors p18 INK4c and p21 Waf1/Cip1 and reduced expression of cyclin D1 (31, 38–40). Recent studies showed that the antiproliferative and anti-inflammatory activities of PPAR{gamma} ligands are mechanistically distinct. PPAR{gamma}-dependent antiproliferative effects involve repression of cyclin D1 via sequestration of p300 and interference with c-fos-directed transcription. Anti-inflammatory effects, independent of this receptor, are mediated via inhibition of the intracellular kinase intracellular {kappa}B kinase, involved in nuclear factor {kappa} B activation (40). Additionally, PPAR{gamma} agonists up-regulate the phosphatase and tension homologue (PTEN) tumor suppressor, suggesting that phosphoinositide signaling pathways are also associated with PPAR{gamma}-mediated growth suppression (41).


   PPAR{alpha} and Cancer
Top
 Abstract
 Introduction
 PPAR{gamma} and Cancer
 PPAR{alpha} and Cancer
PPAR{delta} and Cancer
 PPAR Modulators
 Conclusions
 References
 
Several studies have established a link between PPAR{alpha} activation and epidermal differentiation. Fibrates, which are PPAR{alpha} ligands, induce differentiation and inhibit proliferation of human keratinocytes in vitro (42), and in normal (43) and hyperproliferating (44) mouse skin in vivo, but are inactive in PPAR{alpha}-deficient mice (43). Farnesol also stimulates PPAR{alpha}-dependent differentiation in epidermal keratinocytes (45). Topical PPAR{alpha} agonists have weak preventive effects on tumor promotion in mouse skin, despite up-regulation of PPAR{alpha} in untreated tumors compared with normal epidermis (46). In this regard, PPAR{alpha} expression is also up-regulated in human prostate adenocarcinomas (47). The significance of this observation is as of yet unknown.

Some anticancer actions of phenylacetate may be mediated by PPAR{alpha} activation. The relative potencies of phenylacetate and its analogues as PPAR{alpha} activators correlate strongly to their growth inhibitory effects in human cancer cell lines (48). Phenylacetate also activates PPAR{gamma} (49), making it difficult to ascribe growth-inhibitory effects specifically to activation of the {alpha} isoform. It is important to note that PPAR{alpha} ligands are inactive in tumor cell lines in which PPAR{gamma} ligands are effective antiproliferative agents (8, 9, 25); however, the status of PPAR{alpha} expression in these tumor cell lines is unknown.

In rodents, PPAR{alpha} activation has been associated with both anti- (50, 51) and proinflammatory (52) actions. Opposing effects have also been described in humans. PPAR{alpha} agonists diminish expression of inflammatory markers in human cells and patients treated with fibrates (53, 54). In contrast, expression of the inflammatory mediator COX-2 in human breast and colon cancer cells is up-regulated by PPAR{alpha} agonists (55). The latter finding is particularly troublesome, given that increased COX-2 expression has been specifically linked to enhanced colon cancer risk (reviewed in Ref. 28).

Other possible connections between PPAR{alpha} and cancer prevention come from the inverse association of PPAR{alpha} activation with decreased oxidative stress and aging, both linked with tumorigenesis (reviewed in Ref. 56). PPAR{alpha} agonists administered to aged PPAR{alpha}-replete, but not aged PPAR{alpha}-null mice, decreased tissue levels of lipid peroxides and the oxidant-stress-activated transcription factor nuclear factor {kappa} B (51). Additionally, reduced expression of PPAR{alpha} and peroxisome-associated genes is observed in aged mice; PPAR{alpha} agonists restore expression to levels seen in young animals (57).


   PPAR{delta} and Cancer
Top
 Abstract
 Introduction
 PPAR{gamma} and Cancer
 PPAR{alpha} and Cancer
 PPAR{delta} and Cancer
PPAR Modulators
 Conclusions
 References
 
In contrast to the {gamma} and {alpha} isoforms, activation of PPAR{delta} is associated positively with tumorigenesis. PPAR{delta} transcription is normally suppressed by wild-type APC but is up-regulated in colorectal cancer cells, which have an inactivating APC mutation through enhanced ß-catenin/Tcf-4 binding to TCF-4-responsive elements in the PPAR{delta} promoter (58). Xenografts of PPAR{delta}-null colon cancer cell lines display decreased tumorigenicity in nude mice (59). Consistent with these findings, PPAR{delta} is overexpressed in human and rodent colorectal tumors, as well as preneoplastic colonic mucosa (58, 60, 61). Although initial experiments suggested that nonsteroidal anti-inflammatory drug-induced apoptosis is mediated in part by PPAR{delta} inhibition (58), this was not confirmed in additional studies (59). However, additional experiments in PPAR{delta}-null mice indicate that nonsteroidal anti-inflammatory drug-mediated anti-inflammatory response, which may also be chemopreventive, is at least partially dependent on PPAR{delta} (3).


   PPAR Modulators
Top
 Abstract
 Introduction
 PPAR{gamma} and Cancer
 PPAR{alpha} and Cancer
 PPAR{delta} and Cancer
 PPAR Modulators
Conclusions
 References
 
As suggested by the data presented above (Fig. 1), agonists of PPAR{gamma} and PPAR{alpha}, and antagonists of PPAR{delta}, may find utility as chemopreventive agents. Although no selective PPAR{delta} inhibitors have been identified, a number of agonists for these isoforms has been described. Selective PPAR{gamma} agonists include classic TZDs (troglitazone, rosiglitazone, pioglitazone, and ciglitizone; Refs. 62 and 63) and non-TZD-type agonists. Representatives of the latter include N-(2-benzoylphenyl)-L-tyrosine derivatives, such as GW 1929, GI 262570, and GW 7845, which are among the most potent and selective PPAR{gamma} agonists identified to date (64, 65). GW 0207, a 2,3-disubstituted indole-5-carboxylic acid, is also a potent and selective PPAR{gamma} agonist (66).



View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Chemical structures of PPAR modulators.

 
Fibrates are weak PPAR{alpha} agonists used to treat hyperlipidemia (2). Newer PPAR{alpha} agonists, such as the ureidofibrate GW 9578, are significantly more potent (67) and can be used to study the effects of PPAR{alpha} in neoplasia. If both PPAR{alpha} and PPAR{gamma} are involved in tumorigenesis, dual receptor agonists, such as the TZD KRP-297 (68) and the related isoxazolidinedione derivative JTT-501 (69), may also find utility as chemopreventive agents.

The following compounds can act as partial PPAR{gamma} agonists/antagonists. Although TZD MCC-555 is a low-affinity PPAR{gamma} ligand, it is an effective PPAR{gamma} activator in animals (70). L-764406, a sulfonyl quinoxaline derivative, is a potent and specific PPAR{gamma} ligand and partial agonist that covalently modifies the receptor (71). The thiazolidine acetamide GW 0072 is a high-affinity PPAR{gamma} ligand and weak partial transcriptional activator of the receptor; it is also a potent inhibitor of rosiglitazone-induced adipocyte differentiation (72).

These partial agonists/antagonists display unique biological properties that may translate to distinct therapeutic and/or toxicological profiles, similar to selective estrogen receptor modulators (partial estrogen receptor agonists/antagonists; reviewed in Ref. 28). This is significant, because the selective PPAR{gamma} agonist troglitazone can have rare but serious hepatotoxic consequences (73). Moreover, it is possible that the cancer-promoting effects of PPAR{gamma} ligands, as observed in animals predisposed to colon cancer, can be mitigated using partial agonists.


   Conclusions
Top
 Abstract
 Introduction
 PPAR{gamma} and Cancer
 PPAR{alpha} and Cancer
 PPAR{delta} and Cancer
 PPAR Modulators
 Conclusions
References
 
The PPAR system’s relevance to carcinogenesis is just beginning to be unraveled. Additional research is needed to characterize expression patterns of the various PPAR isoforms in cancerous and precancerous tissue and to determine their precise roles in the carcinogenic process. Numerous fatty acids and their metabolites activate PPAR receptors (74, 75). Thus, PPARs may also provide the missing molecular link between high-fat diets and nutritionally sensitive cancers (76). Although the physiological function of the PPAR was once thought to be restricted to lipid metabolism, it is now clear that these receptors are involved in numerous biological processes. Confirming a crucial role for PPARs in tumorigenesis will foster development of a novel class of cancer preventive drugs (77).


   Footnotes
 
1 To whom requests for reprints should be addressed, at National Cancer Institute, Division of Cancer Prevention, Room 2114, 6130 Executive Boulevard, Bethesda, Maryland 20892-7322 Back

2 The abbreviations used are: PPAR, peroxisome proliferator-activated receptor; AOM, azoxymethane; APC, adenomatous polyposis coli; COX, cyclooxygenase; RXR, retinoic X receptor; TZD, thiazolidinedione. Back

Received 11/26/01; revised 1/24/02; accepted 1/24/02.


   References
Top
 Abstract
 Introduction
 PPAR{gamma} and Cancer
 PPAR{alpha} and Cancer
 PPAR{delta} and Cancer
 PPAR Modulators
 Conclusions
 References
 

  1. Michalik, L., and Wahli, W. Peroxisome proliferator-activated receptors: Three isotypes for a multitude of functions. Curr. Opin. Biotechnol., 10:564 –570,1999 .[CrossRef][Medline]
  2. Willson, T. M., Brown, P. J., Sternbach, D. D., and Henke, B. R. The PPARs: From orphan receptors to drug discovery. J. Med. Chem., 43:527 –550,2000 .[CrossRef][Medline]
  3. Peters, J. M., Lee, S. S. T., Li, W., Ward, J. M., Gavrilova, O., Everett, C., Reitman, M. L., Hudson, L. D., and Gonzalez, F. J. Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor ß({delta}). Mol. Cell. Biol., 20:5119 –5128,2000 .[Abstract/Free Full Text]
  4. Lim, H., Gupta, R. A., Ma, W-G., Paria, B. C., Moller, D. E., Morrow, J. D., DuBois, R. N., Trzaskos, J. M., and Dey, S. K. Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPAR{delta}. Genes Dev., 13:1561 –1574,1999 .[Abstract/Free Full Text]
  5. Gonzalez, F. J., Peters, J. M., and Cattley, R. C. Mechanism of action of the nongenotoxic peroxisome proliferators: role of the peroxisome proliferator-activated receptor {alpha}. J. Natl. Cancer Inst. (Bethesda), 90:1702 –1709,1998 .[Abstract/Free Full Text]
  6. Tontonoz, P., Hu, E., and Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by PPAR{gamma}2, a lipid-activated transcription factor. Cell, 79:1147 –1156,1994 .[CrossRef][Medline]
  7. Fajas, L., Auboeuf, D., Raspe, E., Schoonjans, K., Lefebvre, A-M., Saladin, R., Najib, J., Laville, M., Fruchart, J-C., Deeb, S., Vidal-Puig, A., Flier, J., Briggs, M. R., Staels, B., Vidal, H., and Auwerx, J. The organization, promoter analysis, and expression of the human PPAR{gamma} gene. J. Biol. Chem., 272:18779 –18789,1997 .[Abstract/Free Full Text]
  8. 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., and Spiegelman, B. M. Differentiation and reversal of malignant changes in colon cancer through PPAR{gamma}. Nat. Med., 4:1046 –1052,1998 .[CrossRef][Medline]
  9. Brockman, J. A., Gupta, R. A., and DuBois, R. N. Activation of PPAR{gamma} leads to inhibition of anchorage-independent growth of human colorectal cancer cells. Gastroenterology, 115:1049 –1055,1998 .[CrossRef][Medline]
  10. Tanaka, T., Kohno, H., Yoshitani, S-I., Takashima, S., Okumura, A., Murakami, A., and Hosokawa, M. Ligands for peroxisome proliferator-activated receptors {alpha} and {gamma} inhibit chemically induced colitis and formation of aberrant crypt foci in rats. Cancer Res., 61:2424 –2428,2001 .[Abstract/Free Full Text]
  11. Sarraf, P., Mueller, E., Smith, W. M., Wright, H. M., Kum, J. B., Aaltonen, L. A., de la Chapelle, A., Spiegelman, B. M., and Eng, C. Loss-of-function mutations in PPAR{gamma} associated with human colon cancer. Mol. Cell, 3:799 –804,1999 .[CrossRef][Medline]
  12. Ricote, M., Li, A. C., Willson, T. M., Kelly, C. J., and Glass, C. K. The peroxisome proliferator-activated receptor-{gamma} is a negative regulator of macrophage activation. Nature (Lond.), 391:79 –82,1998 .[CrossRef][Medline]
  13. Jiang, C., Ting, A. T., and Seed, B. PPAR-{gamma} agonists inhibit production of monocyte inflammatory cytokines. Nature (Lond.), 391:82 –86,1998 .[CrossRef][Medline]
  14. Su, C. G., Wen, X., Bailey, S. T., Jiang, W., Rangwala, S. M., Keilbaugh, S. A., Flanigan, A., Murthy, S., Lazar, M. A., and Wu, G. D. A novel therapy for colitis utilizing PPAR-{gamma} ligands to inhibit the epithelial inflammatory response. J. Clin. Investig., 104:383 –389,1999 .[Medline]
  15. Levin, B. Ulcerative colitis and colon cancer: Biology and surveillance. J. Cell. Biochem. Suppl., 16G:47 –50,1992 .
  16. Cottrell, S., Bicknell, D., Kaklamanis, L., and Bodmer, W. F. Molecular analysis of APC mutations in familial adenomatous polyposis and sporadic colon carcinomas. Lancet, 340:626 –630,1992 .[CrossRef][Medline]
  17. Saez, E., Tontonoz, P., Nelson, M. C., Alvarez, J. G., Ming, U. T., Baird, S. M., Thomazy, V. A., and Evans, R. M. Activators of the nuclear receptor PPAR{gamma} enhance colon polyp formation. Nat. Med., 4:1058 –1061,1998 .[CrossRef][Medline]
  18. Lefebvre, A-M., Chen, I., Desreumaux, P., Najib, J., Fruchart, J-C., Geboes, K., Briggs, M., Heyman, R., and Auwerx, J. Activation of the peroxisome proliferator-activated receptor {gamma} promotes the development of colon tumors in C57BL/6J-APC(Min)/+ mice. Nat. Med., 4:1053 –1057,1998 .[CrossRef][Medline]
  19. Mueller, E., Sarraf, P., Tontonoz, P., Evans, R. M., Martin, K. J., Zhang, M., Fletcher, C., Singer, S., and Spiegelman, B. M. Terminal differentiation of human breast cancer through PPAR. Mol. Cell, 1:465 –470,1998 .[CrossRef][Medline]
  20. Elstner, E., Muller, C., Koshizuka, K., Williamson, E. A., Park, D., Asou, H., Shintaku, P., Said, J. W., Heber, D., and 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]
  21. Suh, N., Wang, Y., Williams, C. R., Risingsong, R., Gilmer, T., Willson, T. M., and Sporn, M. B. A new ligand for the peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}), GW7845, inhibits rat mammary carcinogenesis. Cancer Res., 59:5671 –5673,1999 .[Abstract/Free Full Text]
  22. Mehta, R. G., Williamson, E., Patel, M. K., and Koeffler, H. P. A ligand of peroxisome proliferator-activated receptor {gamma}, retinoids, and prevention of preneoplastic mammary lesions. J. Natl. Cancer Inst. (Bethesda), 92:418 –423,2000 .[Abstract/Free Full Text]
  23. Rubin, G. L., Zhao, Y., Kalus, A. M., and Simpson, E. R. Peroxisome proliferator-activated receptor {gamma} ligands inhibit estrogen biosynthesis in human breast adipose tissue: Possible implications for breast cancer therapy. Cancer Res., 60:1604 –1608,2000 .[Abstract/Free Full Text]
  24. Kubota, T., Koshizuka, K., Williamson, E. A., Asou, H., Said, J. W., Holden, S., Miyoshi, I., and 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]
  25. Mueller, E., Smith, M., Sarraf, P., Kroll, T., Aiyer, A., Kaufman, D. S., Oh, W., Demetri, G., Figg, W. D., Zhou, X-P., Eng, C., Spiegelman, B. M., and Kantoff, P. W. Effects of ligand activation of peroxisome proliferator-activated receptor {gamma} in human prostate cancer. Proc. Natl. Acad. Sci. USA, 97:10990 –10995,2000 .[Abstract/Free Full Text]
  26. Butler, R., Mitchell, S. H., Tindall, D. J., and Young, C. Y. F. Nonapoptotic cell death associated with S-phase arrest of prostate cancer cells via the peroxisome proliferator-activated receptor {gamma} ligand, 15-deoxy-{delta} (12,14)-prostaglandin J(2). Cell Growth Differ., 11:49 –61,2000 .[Abstract/Free Full Text]
  27. Hisatake, J-I., Ikezoe, T., Carey, M., Holden, S., Tomoyasu, S., and Koeffler, H. P. Down-regulation of prostate-specific antigen expression by ligands for peroxisome proliferator-activated receptor {gamma} in human prostate cancer. Cancer Res., 60:5494 –5498,2000 .[Abstract/Free Full Text]
  28. Kelloff, G. J. Perspectives on cancer chemoprevention research and drug development. Adv. Cancer Res., 78:199 –334,2000 .[Medline]
  29. Demetri, G. D., Fletcher, C. D. M., Mueller, E., Sarraf, P., Naujoks, R., Campbell, N., Spiegelman, B. M., and Singer, S. Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-{gamma} ligand troglitazone in patients with liposarcoma. Proc. Natl. Acad. Sci. USA, 96:3951 –3956,1999 .[Abstract/Free Full Text]
  30. Nelson, A. R., Fingleton, B., Rothenberg, M. L., and Matrisian, L. M. Matrix metalloproteinases: biologic activity and clinical implications. J. Clin. Oncol., 18:1135 –1149,2000 .[Abstract/Free Full Text]
  31. Chang, T-H., and Szabo, E. Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor {gamma} in non-small cell lung cancer. Cancer Res. 60:1129 –1138,2000 .[Abstract/Free Full Text]
  32. Xin, X., Yang, S., Kowalski, J., and Gerritsen, M. E. Peroxisome proliferator-activated receptor {gamma} ligands are potent inhibitors of angiogenesis in vitro and in vivo. J. Biol. Chem. 274:9116 –9121,1999 .[Abstract/Free Full Text]
  33. Bishop-Bailey, D., and Hla, T. Endothelial cell apoptosis induced by the peroxisome proliferator-activated receptor (PPAR) ligand 15-deoxy-{delta}(12,14)-prostaglandin J(2). J. Biol. Chem., 274:17042 –17048,1999 .[Abstract/Free Full Text]
  34. Kroll, T. G., Sarraf, P., Pecciarini, L., Chen, C-J., Mueller, E., Spiegelman, B. M., and Fletcher, J. A. PAX8-PPAR{gamma}1 fusion in oncogene human thyroid carcinoma. Science (Wash. DC), 289:1357 –1360,2000 .[Abstract/Free Full Text]
  35. Kitamura, S., Miyazaki, Y., Shinomura, Y., Kondo, S., Kanayama, S., and Matsuzawa, Y. Peroxisome proliferator-activated receptor {gamma} induces growth arrest and differentiation markers of human colon cancer cells. Jpn. J. Cancer Res., 90:75 –80,1999 .[CrossRef][Medline]
  36. Motomura, W., Okumara, T., Takahashi, N., Obara, T., and Kohgo, Y. Activation of peroxisome proliferator-activated receptor {gamma} by troglitazone inhibits cell growth through the increase of p27(Kip1) in human pancreatic carcinoma cells. Cancer Res., 60:5558 –5564,2000 .[Abstract/Free Full Text]
  37. Altiok, S., Xu, M., and Spiegelman, B. M. PPAR{gamma} induces cell cycle withdrawal: inhibition of E2F/DP DNA-binding activity via down-regulation of PP2A. Genes Dev., 11:1987 –1998,1997 .[Abstract/Free Full Text]
  38. Morrison, R. F., and Farmer, S. R. Role of PPAR{gamma} in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18(INK4c) and p21(Waf1/Cip1), during adipogenesis. J. Biol. Chem., 274:17088 –17097,1999 .[Abstract/Free Full Text]
  39. Guan, Y-F., Zhang, Y-H., Breyer, R. M., Davis, L., and Breyer, M. D. Expression of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) in human transitional bladder cancer and its role in inducing cell death. Neoplasia, 1:330 –339,1999 .[CrossRef][Medline]
  40. Wang, C., Fu, M., D’Amico, M., Albanese, C., Zhou, J-N., Brownlee, M., Lisanti, M. P., Chatterjee, V. K. K., Lazar, M. A., and Pestell, R. G. Inhibition of cellular proliferation through I{kappa}B kinase-independent and peroxisome proliferator-activated receptor {gamma}-dependent repression of cyclin D1. Mol. Cell. Biol., 21:3057 –3070,2001 .[Abstract/Free Full Text]
  41. Patel, L., Pass, I., Coxon, P., Downes, C. P., Smith, S. A., and Macphee, C. H. Tumor suppressor and anti-inflammatory actions of PPAR{gamma} agonists are mediated via upregulation of PTEN. Curr. Biol., 11:764 –768,2001 .[CrossRef][Medline]
  42. Hanley, K., Jiang, Y., He, S. S., Friedman, M., Elias, P. M., Bikle, D. D., Williams, M. L., and Feingold, K. R. Keratinocyte differentiation is stimulated by activators of the nuclear hormone receptor PPAR{alpha}. J. Investig. Dermatol., 110:368 –375,1998 .[CrossRef][Medline]
  43. Komuves, L. G., Hanley, K., Lefebvre, A-M., Man, M-Q., Ng, D. C., Bikle, D. D., Williams, M. L., Elias, P. M., Auwerx, J., and Feingold, K. R. Stimulation of PPAR{alpha} promotes epidermal keratinocyte differentiation in vivo. J. Investig. Dermatol., 115:353 –360,2000 .[CrossRef][Medline]
  44. Komuves, L. G., Hanley, K., Man, M-Q., Elias, P. M., Williams, M. L., and Feingold, K. R. Keratinocyte differentiation in hyperproliferative epidermis: topical application of PPAR{alpha} activators restores tissue homeostasis. J. Investig. Dermatol., 115:361 –367,2000 .[CrossRef][Medline]
  45. Hanley, K., Komuves, L. G., Ng, D. C., Schoonjans, K., He, S. S., Lau, P., Bikle, D. D., Williams, M. L., Elias, P. M., Auwerx, J., and Feingold, K. R. Farnesol stimulates differentiation in epidermal keratinocytes via PPAR{alpha}. J. Biol. Chem., 275:11484 –11491,2000 .[Abstract/Free Full Text]
  46. Thuillier, P., Anchiraico, G. J., Nickel, K. P., Maldve, R. E., Gimenez-Conti, I., Muga, S. J., Liu, K-L., Fischer, S. M., and Belury, M. A. Activators of peroxisome proliferator-activated receptor-{alpha} partially inhibit mouse skin tumor promotion. Mol. Carcinog., 29:134 –142,2000 .[CrossRef][Medline]
  47. Collett, G. P., Betts, A. M., Johnson, M. I., Pulimood, A. B., Cook, S., Neal, D. E., and Robson, C. N. Peroxisome proliferator-activated receptor {alpha} is an androgen-responsive gene in human prostate and is highly expressed in prostatic adenocarcinoma. Clin. Cancer Res., 6:3241 –3248,2000 .[Abstract/Free Full Text]
  48. Pineau, T., Hudgins, W. R., Liu, L., Chen, L-C., Sher, T., Gonzalez, F. J., and Samid, D. Activation of a human peroxisome proliferator-activated receptor by the antitumor agent phenylacetate and its analogs. Biochem. Pharmacol., 52:659 –667,1996 .[CrossRef][Medline]
  49. Samid, D., Wells, M., Greene, M. E., Shen, W., Palmer, C. N. A., and Thibault, A. Peroxisome proliferator-activated receptor {gamma} as a novel target in cancer therapy: binding and activation by an aromatic fatty acid with clinical antitumor activity. Clin. Cancer Res., 6:933 –941,2000 .[Abstract/Free Full Text]
  50. Devchand, P. R., Keller, H., Peters, J. M., Vazquez, M., Gonzalez, F. J., and Wahli, W. The PPAR{alpha}-leukotriene B4 pathway to inflammation control. Nature (Lond.), 384:39 –43,1996 .[CrossRef][Medline]
  51. Spencer, N. F. L., Poynter, M. E., Im, S-Y., and Daynes, R. A. Constitutive activation of NF-{kappa}B in an animal model of aging. Int. Immunol., 9:1581 –1588,1997 .[Abstract/Free Full Text]
  52. Hill, M. R., Clarke, S., Rodgers, K., Thornhill, B., Peters, J. M., Gonzalez, F. J., and Gimble, J. M. Effect of peroxisome proliferator-activated receptor {alpha} activators on tumor necrosis factor expression in mice during endotoxemia. Infect. Immun., 67:3488 –3493,1999 .[Abstract/Free Full Text]
  53. Delerive, P., De Bossche, K., Besnard, S., Berghe, W. V., Peters, J. M., Gonzalez, F. J., Fruchart, J-C., Tedgui, A., Haegeman, G., and Staels, B. Peroxisome proliferator-activated receptor {alpha} negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-{kappa}B and AP-1. J. Biol. Chem., 274:32048 –32054,1999 .[Abstract/Free Full Text]
  54. Staels, B., Koenig, W., Habib, A., Merval, R., Lebret, M., Torra, I. P., Delerive, P., Fadel, A., Chinetti, G., Fruchart, J-C., Najib, J., Maclouf, J., and Tedgui, A. Activation of human aortic smooth-muscle cells is inhibited by PPAR{alpha} but not by PPAR{gamma} activators. Nature (Lond.), 393:790 –793,1998 .[CrossRef][Medline]
  55. Meade, E. A., McIntyre, T. M., Zimmerman, G. A., and Prescott, S. M. Peroxisome proliferators enhance cyclooxygenase-2 expression in epithelial cells. J. Biol. Chem., 274:8328 –8334,1999 .[Abstract/Free Full Text]
  56. Mates, J. M., Perez-Gomez, C., and Nunez de Castro, I. Antioxidant enzymes and human diseases. Clin. Biochem., 32:595 –603,1999 .[CrossRef][Medline]
  57. Poynter, M. E., and Daynes, R. A. Peroxisome proliferator-activated receptor {alpha} activation modulates cellular redox status, represses nuclear factor-{kappa}B signaling, and reduces inflammatory cytokine production in aging. J. Biol. Chem., 273:32833 –32841,1998 .[Abstract/Free Full Text]
  58. He, T-C., Chan, T. A., Vogelstein, B., and Kinzler, K. W. PPAR{delta} is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell, 99:335 –345,1999 .[CrossRef][Medline]
  59. Park, B. H., Vogelstein, B., and Kinzler, K. W. Genetic disruption of PPAR{delta} decreases the tumorigenicity of human colon cancer cells. Proc. Natl. Acad. Sci. USA, 98:2598 –2603,2001 .[Abstract/Free Full Text]
  60. Gupta, R. A., Tan, J., Krause, W. F., Geraci, M. W., Willson, T. M., Dey, S. K., and DuBois, R. N. Prostacyclin-mediated activation of peroxisome proliferator-activated receptor {delta} in colorectal cancer. Proc. Natl. Acad. Sci. USA, 97:13275 –13280,2000 .[Abstract/Free Full Text]
  61. Roy, H. K., Karolski, W. J., and Ratashak, A. Distal bowel selectivity in the chemoprevention of experimental colon carcinogenesis by the non-steroidal anti-inflammatory drug nabumetone. Int. J. Cancer, 92:609 –615,2001 .[CrossRef][Medline]
  62. Forman, B. M., Tontonoz, P., Chen, J., Brun, R. P., Spiegelman, B. M., and 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 .[CrossRef][Medline]
  63. Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A., Wilkison, W. O., Willson, T. M., and 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]
  64. Henke, B. R., Blanchard, S. G., Brackeen, M. F., Brown, K. K., Cobb, J. E., Collins, J. L., Harrington, W. W., Jr., Hashim, M. A., Hull-Ryde, E. A., Kaldor, I., Kliewer, S. A., Lake, D. H., Leesnitzer, L. M., Lehmann, J. M., Lenhard, J. M., Orband-Miller, L. A., Miller, J. F., Mook, R. A., Jr., Noble, S. A., Oliver, W., Jr., Parks, D. J., Plunket, K. D., Szewczyk, J. R., and Willson, T. M. N-(2-benzoylphenyl)-L-tyrosine PPAR{gamma} agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J. Med. Chem., 41:5020 –5036,1998 .[CrossRef][Medline]
  65. Cobb, J. E., Blanchard, S. G., Boswell, E. G., Brown, K. K., Charifson, P. S., Cooper, J. P., Collins, J. L., Dezube, M., Henke, B. R., Hull-Ryde, E. A., Lake, D. H., Lenhard, J. M., Oliver, W., Jr., Oplinger, J., Pentti, M., Parks, D. J., Plunket, K. D., and Tong, W. N-(2-benzoylphenyl)-L-tyrosine PPAR{gamma} agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent. J. Med. Chem., 41:5055 –5069,1998 .[CrossRef][Medline]
  66. Henke, B. R., Adkison, K. K., Blanchard, S. G., Leesnitzer, L. M., Mook, R. A., Jr., Plunket, K. D., Ray, J. A., Roberson, C., Unwalla, R., and Willson, T. M. Synthesis and biological activity of a novel series of indole-derived PPAR{gamma} agonists. Bioorg. Med. Chem. Lett., 9:3329 –3334,1999 .[CrossRef][Medline]
  67. Brown, P. J., Winegar, D. A., Plunket, K. D., Moore, L. B., Lewis, M. C., Wilson, J. G., Sundseth, S. S., Koble, C. S., Wu, Z., Chapman, J. M., Lehmann, J. M., Kliewer, S. A., and Willson, T. M. A ureido-thioisobutyric acid (GW9578) is a subtype-selective PPAR{alpha} agonist with potent lipid-lowering activity. J. Med. Chem., 42:3785 –3788,1999 .[CrossRef][Medline]
  68. Murakami, K., Tobe, K., Ide, T., Mochizuki, T., Ohashi, M., Akanuma, Y., Yazaki, Y., and Kadowaki, T. A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-{alpha} (PPAR-{alpha}) and PPAR-{gamma}: Effect of PPAR-{alpha} activation on abnormal lipid metabolism in liver of Zucker fatty rats. Diabetes, 47:1841 –1847,1998 .[Abstract]
  69. Shibata, T., Matsui, K., Nagao, K., Shinkai, H., Yonemori, F., and Wakitani, K. Pharmacological profiles of a novel oral antidiabetic agent, JTT-501, an isoxazolidinedione derivative. Eur. J. Pharmacol., 364:211 –219,1999 .[CrossRef][Medline]
  70. Reginato, M. J., Bailey, S. T., Krakow, S. L., Minami, C., Ishii, S., Tanaka, H., and Lazar, M. A. A potent antidiabetic thiazolidinedione with unique peroxisome proliferator-activated receptor {gamma}-activating properties. J. Biol. Chem., 273:32679 –32684,1998 .[Abstract/Free Full Text]
  71. Elbrecht, A., Chen, Y., Adams, A., Berger, J., Griffin, P., Klatt, T., Zhang, B., Menke, J., Zhou, G., Smith, R. G., and Moller, D. E. L-764406 is a partial agonist of human peroxisome proliferator-activated receptor {gamma}. J. Biol. Chem., 274:7913 –7922,1999 .[Abstract/Free Full Text]
  72. Oberfield, J. L., Collins, J. L., Holmes, C. P., Goreham, D. M., Cooper, J. P., Cobb, J. E., Lenhard, J. M., Hull-Ryde, E. A., Mohr, C. P., Blanchard, S. G., Parks, D. J., Moore, L. B., Lehmann, J. M., Plunket, K., Miller, A. B., Milburn, M. V., Kliewer, S. A., and Willson, T. M. A peroxisome proliferator-activated receptor {gamma} ligand inhibits adipocyte differentiation. Proc. Natl. Acad. Sci. USA, 96:6102 –6106,1999 .[Abstract/Free Full Text]
  73. Schoonjans, K., and Auwerx, J. Thiazolidinediones. An update. Lancet, 355:1008 –1010,2000 .[CrossRef][Medline]
  74. Xu, H. E., Lambert, M. H., Montana, V. G., Parks, D. J., Blanchard, S. G., Brown, P. J., Sternbach, S. G., Lehmann, J. M., Wisely, G. B., Willson, T. M., Kliewer, S. A., and Milburn, M. V. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol. Cell, 3:397 –403,1999 .[CrossRef][Medline]
  75. Krey, G., Braissant, O., L’Horset, F., Kalkhoven, E., Perroud, M., Parker, M. G., and Wahli, W. Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol. Endocrinol., 11:779 –791,1997 .[Abstract/Free Full Text]
  76. Willett, W. C., and MacMahon, B. Diet and cancer–an overview. N. Engl. J. Med., 310:697 –703,1984 .[Medline]
  77. Sporn, M. B., Suh, N., and Mangelsdorf, D. J. Prospects for prevention and treatment of cancer with selective PPAR{gamma} modulators (SPARMs). Trends Mol. Med., 7:395 –400,2001 .[CrossRef][Medline]
  78. Tsubouchi, Y., Sano, H., Kawahito, Y., Mukai, S., Yamada, R., Kohno, M., Inoue, K-I., Hla, T., and Kondo, M. Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-{gamma} agonists through induction of apoptosis. Biochem. Biophys. Res. Commun., 270:400 –405,2000 .[CrossRef][Medline]
  79. Fujimura, S., Suzumiya, J., Nakamura, K., and Ono, J. Effects of troglitazone on the growth and differentiation of hematopoietic cell lines. Int. J. Oncol., 13:1263 –1267,1998 .[Medline]
  80. Takahashi, N., Okumura, T., Motomura, W., Fujimoto, Y., Kawabata, I., and Kohgo, Y. Activation of PPAR{gamma} inhibits cell growth and induces apoptosis in human gastric cancer cells. FEBS Lett., 455:135 –139,1999 .[CrossRef][Medline]
  81. Shappell, S. B., Gupta, R. A., Manning, S. Whitehead, R., Boeglin, W. E., Schneider, C., Case, T., Price, J., Jack, G. S., Wheeler, T. M., Matusik, R. J., Brash, A. R., and DuBois, R. N. 15S-Hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor {gamma} and inhibits proliferation in PC3 prostate carcinoma cells. Cancer Res., 61:497 –503,2001 .[Abstract/Free Full Text]
  82. Tontonoz, P., Singer, S., Forman, B. M., Sarraf, P., Fletcher, J. A., Fletcher, C. D. M., Brun, R. P., Mueller, E., Altiok, S., Oppenheim, H., Evans, R. M., and 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]
  83. Han, S. W., Greene, M. E., Pitts, J., Wada, R. K., and Sidell, N. Novel expression and function of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) in human neuroblastoma cells. Clin. Cancer Res., 7:98 –104,2001 .[Abstract/Free Full Text]
  84. Clay, C. E., Namen, A., Atsumi, G-I., Willingham, M. C., High, K. P., Kute, T. E., Trimboli, A. J., Fonteh, A. N., Dawson, P. A., and Chilton, F. H. Influence of J series prostaglandins on apoptosis and tumorigenesis of breast cancer cells. Carcinogenesis (Lond.), 20:1905 –1911,1999 .[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 JCOHome page
V. C. Jordan and B. W. O'Malley
Selective Estrogen-Receptor Modulators and Antihormonal Resistance in Breast Cancer
J. Clin. Oncol., December 20, 2007; 25(36): 5815 - 5824.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
J. A. Crowell, V. E. Steele, and J. R. Fay
Targeting the AKT protein kinase for cancer chemoprevention
Mol. Cancer Ther., August 1, 2007; 6(8): 2139 - 2148.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
L. Kopelovich, J. R. Fay, C. C. Sigman, and J. A. Crowell
The Mammalian Target of Rapamycin Pathway as a Potential Target for Cancer Chemoprevention
Cancer Epidemiol. Biomarkers Prev., July 1, 2007; 16(7): 1330 - 1340.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
A. I. Neugut, B. Lebwohl, and D. L. Hershman
Cancer Chemoprevention: How Do We Know What Works?
J. Clin. Oncol., April 20, 2007; 25(12): 1461 - 1462.
[Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Xu, C. Han, K. Lim, and T. Wu
Cross-talk between Peroxisome Proliferator-Activated Receptor {delta} and Cytosolic Phospholipase A2{alpha}/Cyclooxygenase-2/Prostaglandin E2 Signaling Pathways in Human Hepatocellular Carcinoma Cells
Cancer Res., December 15, 2006; 66(24): 11859 - 11868.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. Xu, C. Han, and T. Wu
A Novel Positive Feedback Loop between Peroxisome Proliferator-activated Receptor-{delta} and Prostaglandin E2 Signaling Pathways for Human Cholangiocarcinoma Cell Growth
J. Biol. Chem., November 10, 2006; 281(45): 33982 - 33996.
[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
 Molecular Cancer TherapeuticsHome page
K. Yamaguchi, S.-H. Lee, T. E. Eling, and S. J. Baek
A novel peroxisome proliferator-activated receptor {gamma} ligand, MCC-555, induces apoptosis via posttranscriptional regulation of NAG-1 in colorectal cancer cells
Mol. Cancer Ther., May 1, 2006; 5(5): 1352 - 1361.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
Y. Yin, H. Yuan, C. Wang, N. Pattabiraman, M. Rao, R. G. Pestell, and R. I. Glazer
3-Phosphoinositide-Dependent Protein Kinase-1 Activates the Peroxisome Proliferator-Activated Receptor-{gamma} and Promotes Adipocyte Differentiation
Mol. Endocrinol., February 1, 2006; 20(2): 268 - 278.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. Lu, K. Imamura, S. Nomura, K.-i. Mafune, A. Nakajima, T. Kadowaki, N. Kubota, Y. Terauchi, G. Ishii, A. Ochiai, et al.
Chemopreventive Effect of Peroxisome Proliferator-Activated Receptor {gamma} on Gastric Carcinogenesis in Mice
Cancer Res., June 1, 2005; 65(11): 4769 - 4774.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. Yin, R. G. Russell, L. E. Dettin, R. Bai, Z.-L. Wei, A. P. Kozikowski, L. Kopleovich, and R. I. Glazer
Peroxisome Proliferator-Activated Receptor {delta} and {gamma} Agonists Differentially Alter Tumor Differentiation and Progression during Mammary Carcinogenesis
Cancer Res., May 1, 2005; 65(9): 3950 - 3957.
[Abstract] [Full Text] [PDF]