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Repression of Beta-Catenin Function in Malignant Cells by Nonsteroidal

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Repression of Beta-Catenin Function in Malignant Cells by Nonsteroidal Repression of ␤-catenin function in malignant cells by nonsteroidal antiinflammatory drugs Desheng Lu*†, Howard B. Cottam*, Maripat Corr‡, and Dennis A. Carson*† *Rebecca and John Moores Cancer Center and ‡Division of Rheumatology, Allergy, and Immunology, University of California at San Diego, La Jolla, CA 92093 Contributed by Dennis A. Carson, October 27, 2005 Activation of the Wnt͞␤-catenin pathway promotes the develop- synthetic ligands of PPAR-␥, such as troglitazone, can prevent ment of several cancers and is an attractive target for chemopre- the development of colon, prostate, and breast cancer in some ventive and chemotherapeutic agents. Nonsteroidal antiinflamma- animal models (36–38). Recently, the NSAID-like molecule tory drugs (NSAIDs) have been reported to antagonize ␤-catenin R-etodolac was also reported to bind the PPAR-␥ coactivator function, but their mechanism of action is not known. We dem- retinoid X receptor ␣ (RXR-␣) (39). However, it is not clear how onstrate here that interference with ␤-catenin function by NSAIDs the functions of ␤-catenin, RXR-␣, and PPAR-␥ are connected. does not correlate with cyclooxygenase (COX) inhibition. Instead, Indeed, some transgenic mice that express constitutively active NSAID inhibition of ␤-catenin requires the high level expression of PPAR-␥ have accelerated mammary gland tumors, compared peroxisome proliferator-activated receptor ␥ (PPAR-␥) and its co- with control animals from the same strains (40). receptor retinoid-X-receptor ␣ (RXR-␣). Immunoprecipitation ex- Activating ligands for different nuclear hormone receptors, periments show that ␤-catenin interacts with RXR-␣ and PPAR-␥ in including retinoid, androgen, and vitamin D receptors, have some malignant cells. Repression of ␤-catenin-dependent tran- been reported to inhibit ␤-catenin-dependent transcription, scription by NSAIDs is thus indirect and depends on the coexpres- possibly by competition for a common pool of cofactors (41–44). sion of other nuclear receptors. The phenomenon has been referred to as transrepression. Because NSAIDs can bind PPAR-␥ and RXR-␣, we hypothe- peroxisome proliferator-activated receptor ␥ ͉ retinoid X receptor ␣ sized that their effects on ␤-catenin function might also be attributable to transrepression. The current experiments indi- he long-term ingestion of various nonsteroidal antiinflam- cate that NSAIDs efficiently inhibit ␤-catenin function only in Tmatory drugs (NSAIDs) is associated with a reduced inci- cells that coexpress both PPAR-␥ and RXR-␣. These results dence of colorectal cancer, and probably of prostate and breast have implications for the development and selective use of cancer (1–6). However, the general inhibitors of cyclooxygenases NSAID-like drugs as cancer chemopreventive and chemother- (COX) have side effects that preclude their use in the general apeutic agents. population (7–9). The development of the more specific COX-2 inhibitors was an effort to overcome this problem. Unfortu- Materials and Methods nately, these drugs may increase the risk of cardiovascular R-etodolac was prepared by fractional crystallization from phar- diseases (10–14). Accordingly, there is a major therapeutic need maceutical grade tablets of racemic etodolac as described (45). for agents that retain the chemopreventive actions of NSAIDs, The enantiomeric purity was Ͼ97% as assayed by HPLC on a but that are devoid of their potential toxicities. chiral column (AGP, ChromTech, Hagersten, Sweden). The Activation of the multifunctional protein ␤-catenin has been PPAR-␣ activator WY14,643 was purchased from ChemSyn shown to play a critical role in the development of colorectal Laboratory (Lenexa, KS). Unless otherwise indicated, other cancer and has been implicated in prostate and breast cancer as reagents were from Sigma. well (15–21). Wnt ligand interaction with a seven-transmem- ␥ brane receptor of the frizzled family induces a signaling cascade Plasmids. The PPAR- reporter plasmid p(AOX)3-TK-Luc, and wherein molecular complexes are recruited close to the mem- the expression vectors for PPAR-␥, PPAR-␥EA469, and RXR-␣ brane. The disheveled (Dsh) protein alters axin interactions, have been described, and were kindly provided by C. Glass which then results in the release of ␤-catenin from a cytoplasmic (University of California at San Diego) (46). The PPAR- complex (22–24). Unphosphorylated ␤-catenin migrates to the ␥EA469 expression vector has a mutation in the AF2 domain nucleus (25–27). There, it associates with transcription factors of that destroys its transactivation, transrepression, and coactivator the T cell factor (TCF) and lymphocyte-enhancing factor (LEF) interactions (47). The ␤-catenin expression plasmid, and the ␤-catenin-dependent TCF͞LEF TOPflash reporter plasmid family, as well as with various transcriptional cofactors, to form MEDICAL SCIENCES multiprotein complexes that regulate genes important for pro- were gifts from H. Clevers (University of Utrecht, Utrecht, The liferation, differentiation, and apoptosis (21, 28). Netherlands). An expression plasmid for human Dsh was pur- Different NSAIDs have been demonstrated to inhibit the chased from Origene Technologies (Rockville, MD). S. Ho activity of ␤-catenin-dependent reporter genes in malignant cell (University of California at San Diego) provided the expression lines, and to induce ␤-catenin degradation (29–34). Moreover, plasmid for nuclear factor of activated T cells (NFAT) (48). The the colonic polyps of patients treated with NSAIDs have reduced expression plasmids pCMX␤gal and H-RasV12 have been de- nuclear accumulation of ␤-catenin (29). The biochemical and scribed (49). The pAP-1 and pNFAT-Luc reporter plasmids clinical data imply that NSAIDs inhibit ␤-catenin activity or its stability (31, 32). However, the biochemical basis for these effects is uncertain, insofar as NSAIDs have not been shown to Conflict of interest statement: No conflicts declared. interact directly with ␤-catenin. Abbreviations: NSAID, nonsteroidal antiinflammatory drug; COX, cyclooxygenase; TCF, T cell factor; LEF, lymphoid-enhancing factor; PPAR, peroxisome proliferator-activated re- At concentrations far higher than those required to inhibit ceptor; RXR-␣, retinoid X receptor ␣; PBP, PPAR-binding protein; Dsh, dishevelled; RA, COX-1 and COX-2, NSAIDs can weakly interact with the retinoic acid; NFAT, nuclear factor of activated T cells. nuclear hormone receptor peroxisome proliferator-activated †To whom correspondence may be addressed. E-mail: [email protected] or dcarson@ receptor-␥ (PPAR-␥) (35). The binding could be related to the ucsd.edu. chemopreventive actions of the drugs, because high-affinity © 2005 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0509316102 PNAS ͉ December 20, 2005 ͉ vol. 102 ͉ no. 51 ͉ 18567–18571 ␮g of reporter plasmid, 0.1–0.2 ␮g of control plasmid pCMX␤gal, 0.1–0.2 ␮g of expression plasmid, and carrier DNA pBluescriptKSII for a total of 1 ␮g per well. After overnight incubation, the cells were washed and given fresh medium that contained 0.5% FBS supplemented with the different drugs, as indicated in the figure legends. If DMSO was used, the control cultures received the same solvent. For luciferase assays, cells were lysed in potassium phosphate buffer containing 1% Triton X-100, and light emission was detected in the presence of luciferin by using a microtiter plate luminometer (MicroBeta TriLux, Gaithersburg, MD). The luciferase values were normal- ized for variations in transfection efficiency by using the ␤-gal Fig. 1. NSAIDs inhibit Dsh͞PPAR-␥͞RXR-␣-mediated transcription. HEK293 internal control, and are expressed either as relative luciferase ͞ cells were transfected with a TCF LEF-dependent reporter gene, expression units (RLU) or as fold stimulation of luciferase activity com- plasmids for Dsh, RXR-␣, and either active PPAR-␥ (A) or inactive PPAR-␥EA469 (B). After overnight incubation, the cells were treated for 24 h with 250 ␮M pared with the designated control cultures. All of the transfec- R-etodolac, 125 ␮M indomethacin, 250 ␮M sulindac, 200 ␮M fenoprofen, 300 tion results represent means of a minimum of three independent ␮M salsalate, and 250 ␮M naproxen or vehicle alone, after which the reporter transfections assayed in duplicate, Ϯ SEM. gene activity was measured. All cells were also transfected with a ␤-gal reporter gene to control for transfection efficiency. The results are expressed Immunoprecipitation and Immunoblotting. Cells were washed twice as % control TCF͞LEF-dependent reporter gene activity Ϯ SEM (n ϭ 3). with PBS and collected in 0.5 ml of lysis buffer (20 mM Tris⅐HCl, pH 8.0͞10% glycerol͞5 mM MgCl2͞0.15 M KCl͞0.1% Nonidet P-40͞protease inhibitors). The lysates of 0.5 to 1 ϫ 107 cells were were purchased from BD Biosciences. The UAS-TK-Luc re- ␥ incubated overnight at 4°C with saturating amounts of agarose porter for Gal4, and expression plasmids for Gal4, Gal4-PPAR- beads linked to monoclonal antibodies specific for ␤-catenin or binding protein (PBP), and VP16 for the mammalian two-hybrid PPAR-␥ (Santa Cruz Biotechnology). The beads were washed ␥ system have been described (50, 51). The VP16-PPAR- expres- twice with lysis buffer and once with PBS. Bound proteins were ␥ sion vector was constructed by ligating PPAR- cDNA into the eluted by boiling the samples in SDS sample buffer and were corresponding KpnI and NheI sites of the pVP16 vector. then resolved by 10% SDS͞PAGE and transferred to nitrocel- lulose membranes. Cell Culture and Transfections.
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