Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conjugated linoleic acid (CLA) is a naturally occurring fatty acid, which has been shown to exert beneficial effects against breast carcinogenesis. It has been reported that CLA could modulate cellular proliferation and differentiation through the activation of peroxisome proliferator-activated receptors (PPARs). Among different PPAR isotypes, PPAR gamma is involved in growth inhibition of transformed cells. Ligands of PPAR gamma are considered as potential anticancer drugs, so CLA was tested for its ability to induce PPAR gamma expression in MCF-7 breast cancer cells. The effects of CLA and of a specific synthetic PPAR gamma antagonist were evaluated on cell growth as well as on parameters responsible for cell growth regulation. We demonstrated here that CLA stimulated the expression of PPAR gamma to levels up to control and caused PPAR gamma translocation into the nucleus. Furthermore, the overexpression of PPAR gamma positively correlates with the inhibition of cell proliferation and with the modulation of ERK signaling induced by CLA; in all cases the administration of the antagonist reverted CLA effects. The PPAR-signaling pathway is connected with the beta-catenin/E-cadherin pathway, thus we evaluated CLA effects on the expression and cellular distribution of these proteins, which are involved in cell adhesion and responsible for invasive behavior. The treatment with CLA determined the up-regulation and the redistribution of beta-catenin and E-cadherin and the antagonist reverted only the effect on beta-catenin. These studies indicate that CLA regulates PPAR gamma expression by selectively acting as an agonist and may influence cell-cell adhesion and invasiveness of MCF-7 cells.
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PMID:Involvement of PPAR gamma and E-cadherin/beta-catenin pathway in the antiproliferative effect of conjugated linoleic acid in MCF-7 cells. 1735 22

Recent reports have shown that peroxisome proliferator-activated receptor (PPAR)alpha ligands reduce growth of some types of malignant tumors and prevent carcinogenesis. In this study, we investigated the inhibitory effect of clofibric acid (CA), a ligand for PPARalpha on growth of ovarian malignancy, in in vivo and in vitro experiments using OVCAR-3 and DISS cells derived from human ovarian cancer and aimed to elucidate the molecular mechanism of its antitumor effect. CA treatment significantly suppressed the growth of OVCAR-3 tumors xenotransplanted s.c. and significantly prolonged the survival of mice with malignant ascites derived from DISS cells as compared with control. CA also dose-dependently inhibited cell proliferation of cultured cell lines. CA treatment increased the expression of carbonyl reductase (CR), which promotes the conversion of prostaglandin E(2) (PGE(2)) to PGF(2alpha), in implanted OVCAR-3 tumors as well as cultured cells. CA treatment decreased PGE(2) level as well as vascular endothelial growth factor (VEGF) amount in both of OVCAR-3-tumor and DISS-derived ascites. Reduced microvessel density and induced apoptosis were found in solid OVCAR-3 tumors treated by CA. Transfection of CR expression vector into mouse ovarian cancer cells showed significant reduction of PGE(2) level as well as VEGF expression. These results indicate that CA produces potent antitumor effects against ovarian cancer in conjunction with a reduction of angiogenesis and induction of apoptosis. We conclude that CA could be an effective agent in ovarian cancer and should be tested alone and in combination with other anticancer drugs.
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PMID:Clofibric acid, a peroxisome proliferator-activated receptor alpha ligand, inhibits growth of human ovarian cancer. 1743 Nov 16

Suppression of colon carcinogenesis by peroxisome proliferator-activated receptor (PPAR)-gamma is likely due to some effect of PPAR-gamma on normal colonic epithelial cells. However, our understanding of the effects of PPAR-gamma in such cells is limited. We analyzed the abundance, distribution, and function of PPAR-gamma in epithelial cells isolated from the murine proximal and distal colon. Marked differences in PPAR-gamma abundance and distribution were observed, suggesting tissue-specific responses. Analysis of PPAR-gamma effects on DNA synthesis, formation of preneoplastic lesions, and activation of MAPK signaling in proximal and distal colonic epithelial cells in vivo indicates that PPAR-gamma regulates both tissue-specific and common responses within the proximal and distal colon. Three major functional cohorts of PPAR-gamma target genes were identified by genomic profiling of isolated colonic epithelial cells: genes that are involved in metabolism, in signaling, and in cellular adhesion and motility. Two subsets of PPAR-gamma target genes were differentially expressed in the proximal and distal epithelium. Proximal target genes were primarily involved in metabolic activities, whereas signal transduction, adhesion, and motility targets were more pronounced in the distal colon. Remarkably, those target genes that are differentially expressed in the proximal colon were all induced on activation of PPAR-gamma, whereas all target genes that are preferentially expressed in the distal colon were repressed. Our data indicate that PPAR-gamma exerts both common and tissue-specific effects in the colon and challenge the general conclusions that PPAR-gamma is induced on differentiation of colonic epithelial cells and that this receptor stimulates differentiated function in epithelial cells throughout the colon.
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PMID:Differential expression, distribution, and function of PPAR-gamma in the proximal and distal colon. 1751 61

Ligands for peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) increase skeletal muscle fatty acid catabolism, improve insulin sensitivity, increase serum high-density lipoprotein cholesterol, elicit anti-inflammatory activity and induce terminal differentiation. Contradictory findings are also reported suggesting that PPARbeta/delta ligands potentiate tumorigenesis by increasing cell proliferation, by inhibiting apoptosis through phosphorylation of Akt and by increasing cyclooxygenase-2 (COX2) and vascular endothelial growth factor (VEGF) expression. The contradictory findings could be due to differences in the model system (cancer cell line versus in vivo), differences in cell culture conditions (with and without serum) or differences in ligands. The present study examined the effect of two different PPARbeta/delta ligands (GW0742 and GW501516) in human cancer cell lines (HT29, HCT116, LS-174T, HepG2 and HuH7) cultured in the presence or absence of serum and compared in vitro analysis with in vivo analysis. Neither PPARbeta/delta ligand increased cell growth or phosphorylation of Akt and no increase in the expression of VEGF or COX2 were detected in any cancer cell line in the presence or absence of serum. Similarly, liver, colon and colon polyps from mice administered these PPARbeta/delta ligands in vivo did not exhibit changes in these markers. Results from these studies demonstrate that serum withdrawal and/or differences in ligands do not underlie the disparity in responses reported in the literature. The quantitative nature of the present findings are inconsistent with the hypothesis that cancer cell lines respond differentially as compared with normal cells, and provide further evidence that PPARbeta/delta ligands do not potentiate tumorigenesis.
Carcinogenesis 2007 Dec
PMID:Peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) ligands do not potentiate growth of human cancer cell lines. 1769 64

Cyclooxygenase (COX) 2-derived prostaglandin E(2) (PGE(2)) promotes colorectal carcinoma growth and invasion, and inhibition of COX2 by non-steroidal anti-inflammatory drugs is known to inhibit these processes. There is controversy regarding the effect of ligand activation of peroxisome proliferator-activated receptor (PPAR)-beta/delta on colon carcinogenesis, although collective evidence from independent laboratories suggest that ligand activation of PPARbeta/delta leads to the induction of terminal differentiation coupled with inhibition of cell growth in a variety of models. The present study examined the hypothesis that ligand activation of PPARbeta/delta and inhibition of COX2 attenuate colon cancer through independent mechanisms and that combining these two mechanisms will enhance this inhibition. Colon cancer was induced by administering azoxymethane to wild-type and PPARbeta/delta-null mice. Cohorts of mice were treated with GW0742 (a PPARbeta/delta ligand), nimesulide (a COX2 inhibitor) or a combination of GW0742 and nimesulide. Inhibition of COX2 by nimesulide attenuated colon cancer and ligand activation of PPARbeta/delta by GW0742 had inhibitory effects. However, the combined treatment of GW0742 and nimesulide did not cause an enhancement in the attenuation of colon cancer. Mechanistically, the effects of these compounds occurred through independent mechanisms as increased levels of differentiation markers as a result of ligand activation of PPARbeta/delta were not found with COX2 inhibition, and a reduction in PGE(2) levels resulting from COX2 inhibition was not observed in response to ligand activation of PPARbeta/delta. Results from these studies effectively dissociate COX2 inhibition and PPARbeta/delta activity during colon carcinogenesis.
Carcinogenesis 2008 Jan
PMID:Ligand activation of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) and inhibition of cyclooxygenase 2 (COX2) attenuate colon carcinogenesis through independent signaling mechanisms. 1789 32

Peroxisome proliferator chemicals are classic non-genotoxic carcinogens. These agents cause liver cancers when chronically administered to rats and mice. Peroxisome proliferators include the widely prescribed lipid and cholesterol lowering fibrate drugs. In contrast to the results in rodents, there is no evidence that fibrates are associated with elevated risk of liver cancer or any other neoplasms in humans thus indicating a species difference in the hepatocarcinogenic response. The biological effects of peroxisome proliferators are mediated by the peroxisome proliferator-activated receptor (PPAR)alpha. Pparalpha-null mice are resistant to all of the pleiotropic effects of peroxisome proliferators, including cell proliferation and hepatocarcinogenesis. The mechanism of hepatocellular proliferation involves downregulation of the microRNA let-7c gene by PPARalpha. Let-7c controls levels of proliferative c-myc by destabilizing its mRNA. Thus, upon suppression of let-7c, c-myc mRNA and protein are elevated resulting in enhanced hepatocellular proliferation. In contrast, PPARalpha-humanized mice, that respond to Wy-14,643 by lower serum triglycerides and induction of genes encoding fatty acid metabolizing enzymes, are resistant to peroxisome proliferator-induced cell proliferation and cancer. These mice do not exhibit downregulation of let-7c gene expression thus forming the basis for the resistance to hepatocellular carcinogenesis.
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PMID:PPARalpha: mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators. 1800 36

The epidermis is a very active site of lipid metabolism, and all peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) isoforms are expressed in the epidermis. Activation of PPARalpha, -beta/delta, or -gamma or LXRs stimulates keratinocyte differentiation. Additionally, activation of these receptors also improves permeability barrier homeostasis by a number of mechanisms, including stimulating epidermal lipid synthesis, increasing lamellar body formation and secretion, and increasing the activity of enzymes required for the extracellular processing of lipids in the stratum corneum, leading to the formation of lamellar membranes that mediate permeability barrier function. The stimulation of keratinocyte differentiation and permeability barrier formation also occurs during fetal development, resulting in accelerated epidermal development. PPAR and LXR activation regulates keratinocyte proliferation and apoptosis, and studies have shown that these receptors play a role in cutaneous carcinogenesis. Lastly, PPAR and LXR activation is anti-inflammatory, reducing inflammation in animal models of allergic and irritant contact dermatitis. Because of their broad profile of beneficial effects on skin homeostasis, PPAR and LXR have great potential to serve as drug targets for common skin diseases such as psoriasis, atopic dermatitis, and skin cancer.
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PMID:Thematic review series: skin lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology. 1818 82

Accumulating evidence indicates that activation of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) dampens the inflammation cascade and inhibits tumor growth of the lung, suggesting that it has tumor suppressor functions. We performed a case-control study of 500 incident lung cancer cases and 517 age- and sex frequency-matched cancer-free controls in a Chinese population to investigate the role of 11 selected single nucleotide polymorphisms (SNPs) of PPAR-gamma in the etiology of lung cancer. We found that decreased lung cancer risk was statistically significantly associated with seven SNPs (P = 0.0004 for rs13073869 and 0.0130 for rs1899951 in a dominant model; P = 0.0310 for rs4135247 in a log-additive model; and P = 0.0468 for rs2972162, 0.0175 for rs709151, 0.0172 for rs11715541 and 0.0386 for rs1175543 in an overdominant model). Consistent with these results of single-locus analysis, both the haplotype and the diplotype analyses revealed a protective effect of the haplotype 'AGA' and 'AAA' of rs13073869, rs1899951 and rs4135247. Furthermore, we observed a statistically significant interaction between the rs1899951 and cigarette smoking. Our results indicate that PPAR-gamma polymorphisms and their interaction with smoking may contribute to the etiology of lung cancer. These findings need to be validated in larger, preferably population-based, studies including different ethnic groups.
Carcinogenesis 2008 Feb
PMID:Genetic variants in peroxisome proliferator-activated receptor-gamma gene are associated with risk of lung cancer in a Chinese population. 1818 57

Curcumin, the phytochemical component in turmeric, is used as a dietary spice and a topical ointment for the treatment of inflammation in India for centuries. Curcumin (diferuloylmethane) is relatively insoluble in water, but dissolves in acetone, dimethylsulphoxide, and ethanol. Commercial grade curcumin contains 10-20% curcuminoids, desmethoxycurcumin, and bisdesmethoxycurcumin and they are as effective as pure curcumin. Based on a number of clinical studies in carcinogenesis, a daily oral dose of 3.6 g curcumin has been efficacious for colorectal cancer and advocates its advancement into Phase II clinical studies. In addition to the anticancer effects, curcumin has been effective against a variety of disease conditions in both in vitro and in vivo preclinical studies. The present review highlights the importance of curcumin as an anti-inflammatory agent and suggests that the beneficial effect of curcumin is mediated by the upregulation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation.
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PMID:Mechanism of the Anti-inflammatory Effect of Curcumin: PPAR-gamma Activation. 1827 31

Several peroxisome proliferators enhance CYP1A1 activity, but the mechanisms involved in this enhancement remain unknown. In this study, we examined the effect of troglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, on CYP1A1 gene expression and explored the mechanisms involved in these effects. Troglitazone increased gene expression of CYP1A1 mRNA and also increased CYP1A1-specific 7-ethoxyresorufin-O-deethylase (EROD) activity in a dose-dependent manner. Moreover, concomitant treatment with troglitazone and GW9662, a PPAR antagonist, markedly reduced the troglitazone-inducible EROD activity. Luciferase reporter assays using Hepa-1c1c7 cells showed a significant transactivation by troglitazone with a reporter plasmid containing a region from -1395 to +7 of the CYP1A1 gene. We found that a putative peroxisome proliferator-response element (PPRE) between -521 and -500 is located in the CYP1A1 gene promoter. Their inactivation by deletion mutagenesis suppressed the inductive effect of troglitazone on CYP1A1 promoter activation. Electrophoretic mobility shift assay revealed that troglitazone induced the activation of the PPAR-gamma to a form capable of binding specifically to the PPRE sequence of the CYP1A1 gene promoter. Furthermore, troglitazone increased the formation of the benzo[a]pyrene (BaP)-DNA adduct. Overall, our results suggest that troglitazone induces CYP1A1 enzyme activity and gene expression through PPAR-gamma activation, and may be involved in carcinogenesis.
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PMID:Effect of troglitazone on CYP1A1 induction. 1830 46


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