Target Genes of Peroxisome Proliferator-activated Receptor γ in Colorectal Cancer Cells

Gupta, Rajnish A.; Brockman, Jeffrey A.; Sarraf, Pasha; Willson, Timothy M.; DuBois, Raymond N.

doi:10.1074/jbc.m103779200

Cited by 187 publications

(135 citation statements)

References 61 publications

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“…To determine if this modulation of PPAR␥ expression was reflected in PPAR␥ target genes, RNA levels of lipocalin-2 were measured. 27 A decreased level of lipocalin-2 RNA was seen in the liver and correlated with the reduction in the PPAR␥ protein (Fig. 7).…”

Section: Resultsmentioning

confidence: 99%

Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis

et al. 2007

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A breakdown in intestinal barrier function and increased bacterial translocation are key events in the pathogenesis of sepsis and liver disease. Altering gut microflora with noninvasive and immunomodulatory probiotic organisms has been proposed as an adjunctive therapy to reduce the level of bacterial translocation and prevent the onset of sepsis. The purpose of this study was to determine the efficacy of a probiotic compound in attenuating hepatic and intestinal injury in a mouse model of sepsis. Wild-type and interleukin-10 (IL-10) gene-deficient 129 Sv/Ev mice were fed the probiotic compound VSL#3 for 7 days. To induce sepsis, the mice were injected with lipopolysaccharide (LPS) and D-galactosamine (GalN) in the presence and absence of the peroxisome proliferator-activated receptor gamma (PPAR␥) inhibitor GW9662. The mice were killed after 6 hours, and their colons were removed for the measurement of the cytokine production and epithelial function. The functional permeability was assessed by the mannitol movement and cyclic adenosine monophosphate-dependent chloride secretion in tissue mounted in Ussing chambers. The livers were analyzed for bacterial translocation, cytokine production, histological injury, and PPAR␥ levels. The tissue levels of tumor necrosis factor alpha, interferon gamma, IL-6, and IL-12p35 ribonucleic acid were measured by semiquantitative reverse transcription polymerase chain reaction. L iver dysfunction and failure contribute to the high mortality rates seen in patients with Gram-negative sepsis. The presence of lipopolysaccharide (LPS) from Gram-negative bacteria in the systemic circulation results in the activation of the innate immune system and the secretion of high levels of proinflammatory cytokines. In animal models, LPS challenge can induce a systemic reaction resulting in a sepsis-like condition characterized by fever, hypotension, and widespread tissue damage. D-Galactosamine (GalN) increases the susceptibility of mice to LPS-induced shock by impairing liver metabolism. 1 Challenging mice with low doses of LPS in conjunction with GalN results in massive liver apoptosis and increased mortality.Tumor necrosis factor alpha (TNF-␣) plays a central role in the overwhelming systemic inflammatory response to LPS. 2 However, the complete blockade of TNF-␣ production does not improve survival in animals or humans 3 The activation of nuclear factor kappa B (NF-B) has been shown to play a key role in the pathogenesis of sepsis and is a pivotal step in the regulation of several immune and proinflammatory genes, including TNF-␣. 4 The modulation of NF-B activity has been proposed as a strategy for reducing the mortality associated with sepsis. Peroxisome proliferator-activated receptor gamma (PPAR␥) is a nuclear hormone receptor and transcription

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Section: Resultsmentioning

confidence: 99%

Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis

et al. 2007

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“…15dPGJ 2 negatively regulates myogenesis in part by inhibition of MyoD gene expression (47), and DuBois and colleagues (33) used microarray technology to show that inhibition of colon cancer cell growth by the PPAR␥-selective ligand BRL49653 is associated with inhibition of RegIA and Gob4, genes critical to growth and maturation of colonic epithelial cells. Our data suggest that early expression of p21 and p27 may be required for 15dPGJ 2 -induced apoptosis in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Early de Novo Gene Expression Is Required for 15-Deoxy-Δ12,14-prostaglandin J2-induced Apoptosis in Breast Cancer Cells

Clay¹,

Atsumi²,

High³

et al. 2001

Journal of Biological Chemistry

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Cyclopentenone prostaglandin derivatives of arachidonic acid are potent inducers of apoptosis in a variety of cancer cell types. Several investigators have shown that the terminal derivative of prostaglandin J 2 (PGJ 2 ) metabolism, 15-deoxy-⌬ 12,14 -PGJ 2 (15dPGJ 2 ), induces apoptosis in breast cancer cells and is a potent activator of the nuclear hormone receptor peroxisome proliferator-activated receptor ␥ (PPAR␥), but 15dPGJ 2 effects can be mediated by PPAR␥-dependent and PPAR␥-independent mechanisms. Here we report that 15dPGJ 2 regulates early gene expression critical to apoptosis. Specifically, 15dPGJ 2 induces potent and irreversible S phase arrest that is correlated with expression of genes critical to cell cycle arrest and apoptosis, including the cyclin-dependent kinase inhibitor p21Waf1/Cip1 (p21). Inhibition of RNA or protein synthesis abrogates apoptosis induced by 15dPGJ 2 in breast cancer cells but potentiates apoptosis induced by tumor necrosis factor-␣ or CD95/Fas ligand. Additionally, 15dPGJ 2 induces caspase activation that is blocked by peptide caspase inhibitors. These data show that de novo gene transcription is necessary for 15dPGJ 2 -induced apoptosis in breast cancer cells. Critical candidate genes are likely to be revealed through analysis of differential cDNA array expression.Cyclopentenone prostaglandins potently induce cell cycle arrest and apoptosis in a number of cancer cell types (1-13). The terminal derivative of prostaglandin J 2 (PGJ 2 ) 1 metabolism, 15-deoxy-⌬ 12,14 -PGJ 2 (15dPGJ 2 ), is a potent agonist for the peroxisome proliferator-activated receptor ␥ (PPAR␥) (14, 15) and inhibits NFB, AP-1, nuclear factor of activated T-cells, and signal transducers and activators of transcription (16 -20), perhaps via direct physical interaction between these transcription factors (21) or competition for limited transcriptional co-activators (22). Activation of PPAR␥ or inhibition of NFB blocks angiogenesis of endothelial cells and suppresses transcriptional activation of COX-2 (23, 24). Together these observations suggest a variety of cellular pathways through which cyclopentenone prostaglandins may exert potent anti-inflammatory and antineoplastic properties in diverse cell types. Moreover, it was recently shown that cyclopentenone compounds are produced in vivo (25-28). Thus, it is critical to determine which mechanism(s) predominate to further develop these compounds as anticancer agents.These studies demonstrate that 15dPGJ 2 -induced apoptosis in breast cancer cells requires expression of specific gene products. Blocking de novo mRNA and protein expression inhibited 15dPGJ 2 -induced apoptosis. Among the genes up-regulated by 15dPGJ 2 , which may account, at least in part, for cell cycle arrest and apoptosis, are the cyclin-dependent kinase inhibitors p21Waf1/Cip1 (p21) and p27 Kip1 (p27). EXPERIMENTAL PROCEDURESReagents and Cell Culture-15dPGJ 2 was purchased from Cayman Chemical (Ann Arbor, MI). 15dPGJ 2 is rapidly interconverted to a mixture of at least five active isomers...

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“…CEACAM6 probe set "203757_s_at" (carcinoembryonic antigen-related cell adhesion molecule 6), which is a known PPAR␥ target (56), had the greatest positive regulation with a fold change of 2 4.8 . SYNC1…”

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confidence: 99%

“…These cells have sustained an APC loss-of-function mutation followed by loss of heterozygosity of the wildtype APC allele; however, MOSER cells retain TGF␤ sensitivity (54,55) and have wild-type K-Ras, indicating that they represent a late adenoma or early adenocarcinoma stage. Furthermore, PPAR␥ inhibits transformed properties of MOSER cells (56), making them an ideal model to study the mechanism whereby this receptor inhibits early steps in transformation of colonic epithelial cells.…”

mentioning

confidence: 99%

Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

Bush

Havens

Necela

et al. 2007

Journal of Biological Chemistry

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Activation of PPAR␥ in MOSER cells inhibits anchoragedependent and anchorage-independent growth and invasion through Matrigel-coated transwell membranes. We carried out a longitudinal two-class microarray analysis in which mRNA abundance was measured as a function of time in cells treated with a thiazolidinedione PPAR␥ agonist or vehicle. A statistical machine learning algorithm that employs an empirical Bayesian implementation of the multivariate HotellingT2 score was used to identify differentially regulated genes. HotellingT2 scores, MB statistics, and maximum median differences were used as figures of merit to interrogate genomic ontology of these targets. Three major cohorts of genes were regulated: those involved in metabolism, DNA replication, and migration/motility, reflecting the cellular phenotype that attends activation of PPAR␥. The bioinformatic analysis also inferred that PPAR␥ regulates calcium signaling. This response was unanticipated, because calcium signaling has not previously been associated with PPAR␥ activation. Ingenuity pathway analysis inferred that the nodal point in this cross-talk was Down syndrome critical region 1 (DSCR1). DSCR1 is an endogenous calcineurin inhibitor that blocks dephosphorylation and activation of members of the cytoplasmic component of nuclear factor of activated T cells transcription factors. Lentiviral short hairpin RNA-mediated knockdown of DSCR1 blocks PPAR␥ inhibition of proliferation and invasion, indicating that DSCR1 is required for suppression of transformed properties of early stage colorectal cancer cells by PPAR␥. These data reveal a novel, heretofore unappreciated link between PPAR␥ and calcium signaling and indicate that DSCR1, which has previously been thought to function by suppression of the angiogenic response in endothelial cells, may also play a direct role in transformation of epithelial cells.

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Target Genes of Peroxisome Proliferator-activated Receptor γ in Colorectal Cancer Cells

Cited by 187 publications

References 61 publications

Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis

Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis

Early de Novo Gene Expression Is Required for 15-Deoxy-Δ12,14-prostaglandin J2-induced Apoptosis in Breast Cancer Cells

Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

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