Diclofenac Antagonizes Peroxisome Proliferator-Activated Receptor-γ Signaling

Adamson, Douglas; Frew, David; Tatoud, Roger; Wolf, Charles; Palmer, Colin N.A.

doi:10.1124/mol.61.1.7

Cited by 79 publications

(40 citation statements)

References 31 publications

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“…This antagonistic function of R-etodolac was suggested to explain its inhibition of the Wnt/ h-catenin pathway (40). Diclofenac and indomethacin are also NSAIDs capable of both Wnt/h-catenin pathway inhibition and antagonizing strong activation of PPARg (41,42). All three compounds have been shown to bind and activate PPARg.…”

Section: Discussionmentioning

confidence: 99%

A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities

Handeli

Simon

2008

Molecular Cancer Therapeutics

168

143

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Activation of the Wnt/B-catenin signaling pathway occurs in several types of cancers and thus it is an attractive target for anticancer drug development. To identify compounds that inhibit this pathway, we screened a chemical library using a cell-based B-catenin/Tcf -responsive reporter. We identified FH535, a compound that suppresses both Wnt/B-catenin and peroxisome proliferator -activated receptor (PPAR) signaling. FH535 antagonizes both PPAR; and PPARD ligand -dependent activation and shows structural similarity to GW9662, a known PPAR; antagonist. The effect of FH535 on B-catenin/Tcf activity is reduced in cells carrying a deletion of the PPARd gene, as well as by the PPAR; agonist lysophosphatidic acid. Mechanistically, FH535 inhibits recruitment of the coactivators B-catenin and GRIP1 but not the corepressors NCoR and SMRT. Its repression of B-catenin recruitment, in comparison with GW9662, is linked to FH535 ¶s unique capability to inhibit the Wnt/B-catenin signaling pathway. The antiproliferation effect of the compound observed on some transformed colon lung and liver cell lines is suggestive of its potential therapeutic value in the treatment of cancer. [Mol Cancer Ther 2008;7(3):521 -9]

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Section: Discussionmentioning

confidence: 99%

A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities

Handeli

Simon

2008

Molecular Cancer Therapeutics

168

143

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“…Diclofenac is a widely used analgesic, binds to PPAR␥ at clinically relevant concentrations, and also antagonizes PPAR␥ transactivation by rosiglitazone in a receptor-mediated manner in 3T3-L1 preadipocyte cells (32). Treatment of PC12 cells with diclofenac alone did not cause a statistically significant change in the relative ppEnk mRNA levels (Fig.…”

Section: Metabolic Regulation Of Neuronal Genesmentioning

confidence: 99%

Stereospecific Regulation of Tyrosine Hydroxylase and Proenkephalin Genes by Short-Chain Fatty Acids in Rat PC12 Cells

et al. 2004

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Circulating short-chain fatty acids (SCFAs) are primarily derived from bacterial fermentation of carbohydrates in the colon where they function as physiologic modulators of epithelial cell maturation. Butyrate has been shown to induce tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis, and enkephalin neuropeptide gene transcription, suggesting a role in perinatal sympathoadrenal stress-adaptation. We sought to determine whether there were SCFA structural requirements for this effect. Nine biologically relevant SCFAs and butyrate derivatives were tested in an in vitro model (PC12, rat pheochromocytoma cells) for their ability to regulate neurotransmitter-related gene expression. Our results revealed that among all the studied SCFAs, only propionate and butyrate increased tyrosine hydroxylase and proenkephalin mRNA levels. The functional activity was selective to the carbon atom chain length and associated with the presence of an ethyl moiety in the carbon atom backbone chain. Modifications or absence of this domain affected the gene induction response, suggesting a receptor-mediated mechanism(s). Moreover, propionate, butyrate, and the drug 4-phenylbutyrate were each shown to regulate transmitter genes via at least three independent mechanisms: histone hyperacetylation, cAMP signaling, or peroxisome proliferator-activated receptor gamma-mediated pathways. Thus, the biologic impact of SCFAs on catecholaminergic and opioid systems depend on the activation of SCFA-specific, dose-specific, and gene-specific molecular mechanisms. We speculate that 1) circulating levels of SCFAs may influence sympathoadrenal transmitter biosynthesis and hence whole animal stress-adaptive responsiveness after birth, and 2) the adverse effects of antibiotics on delayed acquisition of postnatal gut flora may affect this apparent evolutionary advantage of gut colonization. Sympathoadrenal transmitter systems mature to adult capacity a week or more after birth in response to progressive cholinergic innervation, exposure to growth factors, and hormonal influences from both the hypothalamic-pituitary-adrenal cortical and thyroid hormonal systems (1-6). Although the importance of these conventional control mechanisms is well established, the evolutionary significance of other exogenous stimuli can be considered in a broader view of environmentally derived signal-transduction. For example, the delayed period of adrenal transmitter accumulation after birth coincides with the time taken to establish full enteral feedings, colonization of the intestine, and attendant production of SCFA (7). Moreover, in the rat (as well as in humans), this time frame is far longer than the capacity of the chromaffin cell to rapidly induce biosynthesis of either catecholamines or enkephalins, which can occur in a matter of hours (8)

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“…This study has provided definitive evidence that indomethacin also has similar activity in human CRC cells in vitro, at similar (Ͼ100 M) concentrations to those previously re- jpet.aspetjournals.org ported to activate PPAR␥ (Lehmann et al, 1997;Jaradat et al, 2001;Adamson et al, 2002;Yamazaki et al, 2002). Importantly, negative regulation of PPAR␥ activity at lower concentrations of indomethacin (10 M), compatible with significant COX inhibition in human CRC cells (Kokoska et al, 1999) and other cultured cell types (Kirtikara et al, 2001), but minimal direct PPAR␥ activation (Lehmann et al, 1997;Jaradat et al, 2001;Yamazaki et al, 2002), did not occur in HCT116 cells.…”

Section: Discussionmentioning

confidence: 52%

“…Previous data showing direct binding and transcriptional activation of PPAR␥ by indomethacin has been obtained from experiments on cells (CV-1 and COS-1 cells transfected with human PPAR␥, as well as human rheumatoid synoviocytes) with little relevance to CRC (Lehmann et al, 1997;Jaradat et al, 2001;Adamson et al, 2002;Yamazaki et al, 2002). This study has provided definitive evidence that indomethacin also has similar activity in human CRC cells in vitro, at similar (Ͼ100 M) concentrations to those previously re- jpet.aspetjournals.org ported to activate PPAR␥ (Lehmann et al, 1997;Jaradat et al, 2001;Adamson et al, 2002;Yamazaki et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Activation of Peroxisome Proliferator-Activated Receptor γ Does Not Explain the Antiproliferative Activity of the Nonsteroidal Anti-Inflammatory Drug Indomethacin on Human Colorectal Cancer Cells

Hawcroft¹,

Gardner²

2003

J Pharmacol Exp Ther

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The mechanism of the anticolorectal cancer activity of the nonsteroidal anti-inflammatory drug indomethacin is poorly understood. Indomethacin inhibits both cyclooxygenase (COX) isoforms, but it may also act via COX-independent targets. Indomethacin can bind and activate the transcription factor peroxisome proliferator-activated receptor (PPAR) ␥. Moreover, natural and synthetic PPAR␥ ligands can induce growth arrest and apoptosis of human colorectal cancer cells in vitro. Therefore, we tested the hypothesis that the antiproliferative activity of indomethacin on human colorectal cancer cells in vitro is explained by a PPAR␥-dependent mechanism of action. Human colorectal cancer cell lines SW480 and HCT116 both expressed functional PPAR␥. Indomethacin directly activated PPAR␥ in both cell lines (HCT116 Ͼ SW480). A dominantnegative PPAR␥ strategy was used to demonstrate that endogenous PPAR␥ represses proliferation of HCT116 cells (compatible with tumor suppressor activity) but that the presence of functional PPAR␥ is not necessary for the antiproliferative activity (or reduction in cyclin D1 protein) associated with indomethacin in vitro. In summary, indomethacin (Ͼ100 M) directly activates PPAR␥ in human colorectal cancer cells. However, PPAR␥ activation does not underlie the antineoplastic activity of indomethacin on human colorectal cancer cells in vitro.A substantial body of evidence exists that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticolorectal cancer (CRC) activity (Shiff and Rigas, 1997;Garcia Rodriguez and Huerta-Alvarez, 2001). However, the mechanism(s) of the antineoplastic activity of this class of drugs remains unclear. It is well recognized that the majority of NSAIDs inhibit one or both of the cyclooxygenase (COX)

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Diclofenac Antagonizes Peroxisome Proliferator-Activated Receptor-γ Signaling

Cited by 79 publications

References 31 publications

A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities

A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities

Stereospecific Regulation of Tyrosine Hydroxylase and Proenkephalin Genes by Short-Chain Fatty Acids in Rat PC12 Cells

Activation of Peroxisome Proliferator-Activated Receptor γ Does Not Explain the Antiproliferative Activity of the Nonsteroidal Anti-Inflammatory Drug Indomethacin on Human Colorectal Cancer Cells

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