Peroxisome Proliferator-activated Receptor and Cancers

The peroxisome proliferator-activated receptor (PPAR ) ligands have anticancer activity against a wide variety of neoplastic cells in vitro. Animal studies have chronicled their in vivo anticancer effects and chemopreventive capabilities. In addition, moderate anticancer activities of PPAR ligands with minimal toxicities have been observed in patients with liposarcomas and prostate cancers. These compounds can slow growth and induce partial differentiation of selected cancer cells. They can decrease levels of cyclin D1 and E, inflammatory cytokines, and nuclear factor B and increase expression of p21 and p27. Surprisingly, some or many of these effects may occur independently of PPAR . Other data suggest that PPAR may behave as a tumor suppressor gene, although several compelling murine models, paradoxically, suggest that under selected circumstances, PPAR ligands may stimulate cancer formation. Nevertheless, the bulk of studies showed that PPAR ligands do have antiproliferative activity against many transformed cells and may be helpful in the setting of adjuvant and chemopreventive treatments of several common tumors, including colon, prostate, and breast cancers. Introduction The PPAR 3 is a member of the NHR superfamily (1–4). It functions as a transcription factor after it heterodimerizes with the RXR and binds to specific response elements called peroxisome proliferating response elements (5). To act as a transcription factor, PPAR requires activation by binding its ligand. Furthermore, the RXR member of this complex can also bind simultaneously with its ligand, which can result in enhanced transcriptional activity (6). The activated PPAR /RXR heterodimer attaches to the peroxisome proliferating response element of a target gene, and coactivator proteins are recruited such as p300 (CBP), SRC-1, as well as the Drip205 family of proteins (also know as TRAP 220) to modulate gene transcription (7). Different ligands of PPAR appear to be able to recruit different coactivators (8, 9), which might provide specificity of biological activity of PPAR . Adipocyte tissue has some of the highest levels of PPAR . However, the receptor is expressed in many other tissues and cell types throughout the body, including monocytes and macrophages (10), liver (11–13), skeletal muscle (14), breast (15), prostate (16), colon, and type 2 alveolar pneumocytes. Two PPAR isoforms are derived by alternate promoter usage. Most tissue express the PPAR 1 isoform, whereas the PPAR 2 isoform is specific to adipocytes. Although a formal study has not been reported, cancer cells probably express an equivalent amount of PPAR as their normal counterparts. The 15-deoxy-prostaglandin J2 is a naturally occurring PPAR ligand. This eicosanoid can activate PPAR at micromolar concentrations. Some unsaturated fatty acids also are natural ligands of the receptor. Synthetic PPAR ligands, known as TZDs, include rosiglitazone (Avandia), pioglitazone (Actos), and troglitazone (Rezulin). The latter causes a severe idiosyncratic liver problem and thus has been discontinued. The TZDs are a breakthrough in the therapy of type II diabetes melitis because they decrease insulin resistance. TZDs enhance insulin action by increasing glucose uptake in the peripheral tissue as well as reducing the hepatic glucose output, and a strong correlation occurs between the ability of the ligand to activate PPAR and the antidiabetic potency of the PPAR ligand. A recently synthesized triterpinoid [2-cyano-3,12divoaleana-1,9-diene-28-oic acid] can bind to PPAR and can induce differentiation and inhibit proliferation of a variety of cancer cells; and it has anti-inflammatory activity (17, 18). Most of the known target genes that are transcriptionally activated by PPAR belong to the pathway of metabolism and transport of lipids, including lipoprotein lipase, adipsin, fatty acid binding protein, Acyl-CoA synthase, and fatty acid transport protein. Furthermore, the PPAR can mediate differentiation of the preadipocyte to adipocytes (19–21). The ligands of PPAR can also repress transcription. For example, in monocytes and macrophages, they can lower the expression of cytokines such as IL-4 as well as proinflammatory products, including TNF, IL-1, as well as inducible nitric oxide synthetase (22–26). The proinflammatory transcription factors such as AP1, Stat, and NFB can also be inhibited. The mechanism by which this occurs is unclear. PPAR can form weak interactions with the corepressors NCOR and SMRT (27). On the other hand, the repression produced by these compounds may be independent of acting as a ligand of PPAR (discussed later). The target genes that mediate the anticancer activity of the activated PPAR are unclear. Received 5/2/02; revised 8/12/02; accepted 8/21/02. 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 This review is sponsored, in part, by NIH grants. H. P. K. is a member of the Jonsson Cancer Center, University of California, Los Angeles, and has the endowed Mark Goodson Chair in Oncology Research at Cedars-Sinai Medical Center. 2 To whom requests for reprints should be addressed, at Hematology/ Oncology Division, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, BM1-109, Los Angeles, CA 90048. Phone: (310) 423-4609; Fax: (310) 423-3030. 3 The abbreviations used are: PPAR , peroxisome proliferator-activated receptor ; NHR, nuclear hormone receptor; RXR, retinoid X receptor; TZD, thiazolidinedione; TNF, tumor necrosis factor; IL, interleukin; NFB, nuclear factor B; APC, adenomatous polyposis coli; TCF, T-cell factor; COX-2, cyclooxygenase 2; PSA, prostate-specific antigen. 1 Vol. 9, 1–9, January 2003 Clinical Cancer Research Cancer Research. on October 15, 2017. © 2003 American Association for clincancerres.aacrjournals.org Downloaded from