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)

This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG. Besides detoxifying electrophilic xenobiotics, such as chemical carcinogens, environmental pollutants, and antitumor agents, these transferases inactivate endogenous alpha,beta-unsaturated aldehydes, quinones, epoxides, and hydroperoxides formed as secondary metabolites during oxidative stress. These enzymes are also intimately involved in the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, as well as the degradation of tyrosine. Among their substrates, GSTs conjugate the signaling molecules 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they antagonize expression of genes trans-activated by the peroxisome proliferator-activated receptor gamma (PPARgamma) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-kappaB (NF-kappaB). Cytosolic human GST exhibit genetic polymorphisms and this variation can increase susceptibility to carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG are associated with alterations in lung function and increased risk of myocardial infarction and stroke. Targeted disruption of murine genes has demonstrated that cytosolic GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins have proinflammatory activities. Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products. Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress.
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PMID:Glutathione transferases. 1582 71

Peroxisome proliferator activated receptors (PPARs) is known to be expressed in several cancers, but their roles on carcinogenesis has not been confirmed. PPARalpha and delta have not been defined whether as an accelerator or an inhibitor, but now PPARgamma is thought as an inhibitor on carcinogenesis. Therefore, we attempted to elucidate the role of PPARgamma in gastric carcinogenesis and explore the possibility of using PPARgamma ligand as chemopreventive agent for gastric cancer with PPARgamma knockout mice. The present study demonstrated that PPARgamma suppresses gastric carcinogenesis, the PPARgamma ligand troglitazone is a potential chemopreventive agent for gastric carcinogenesis, and troglitazone's chemopreventive effect is dependent on PPARgamma. Unfortunately, thiazolidinediones such as troglitazone has side effects, including edema at the high dose of administration. So we expect the development of new PPARgamma ligands, which are more selective and powerful for PPARgamma, to break through the difficulties of PPARgamma ligands' use clinically.
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PMID:[Roles of PPARs in carcinogenesis]. 1582 24

Epidemiologic studies suggest that intake of high energy from fat, inducing overweight, increases the risk of cancer development and promotes colon carcinogenesis. It is therefore important to understand which parameters are affected early on by a high-fat diet in order to devise and improve protective nutritional strategies. We investigated the effect of high energy/fat intake on colon mucosa of male Wistar rats induced by a single 1,2-dimethylhydrazine (DMH) injection. Aberrant crypt foci (ACF) were numbered and modifications in cyclooxygenase-2 (COX-2) and beta-catenin levels assessed. Peroxisome proliferator- and retinoic acid-activated receptors (PPAR and RAR, RXR) are key transcription factors regulating gene expression in response to nutrient-activated signals. A short-term study was designed to evaluate whether alterations in mRNA expression of nuclear receptors can be detected at the beginning of the weight gain phase induced by an appetizing hyperlipidic diet (HLD). HLD consumption induced early downregulation of PPARgamma (-33.1%) and RARbeta (-53.1%) mRNA expression concomitant with an increase in levels of COX-2 (+45.5%) and beta-catenin (+84.56%) and in the number of ACF (191.56 +/- 88.60 vs. 21.14 +/- 11.64, p < 0.05). These findings suggest that HLD increases ACF occurrence, possibly through alterations in the mRNA expression profile of nuclear receptors. Moreover, the use HLD rich in retinyl esters or supplemented with all-trans retinoic acid led to a reduction in the number of ACF. Vitamin A also prevented HLD-induced alterations and the increase in levels of COX-2 and beta-catenin. The present observations show a protective role for vitamin A against disturbances associated with HLD exposure in induced colon carcinogenesis.
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PMID:A high-fat diet generates alterations in nuclear receptor expression: prevention by vitamin A and links with cyclooxygenase-2 and beta-catenin. 1585 52

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated transcription factor. There have been suggestions that PPARgamma ligands may have utility in preventing tumor development in rodent mammary glands and colon. The recent finding that mice lacking one allele of the PPARgamma gene were significantly more susceptible to 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis compared to wild-type mice highlights mouse skin as another potential organ in which PPARgamma ligands may be effective as chemopreventive agents. In this study, we assessed the effect of two PPARgamma ligands (rosiglitazone and troglitazone) on UV and DMBA/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin carcinogenesis, two of the most commonly used mouse skin carcinogenesis models. Unexpectedly, neither rosiglitazone (dietary 200 ppm) nor troglitazone (topical 100 microg) significantly inhibited UV-induced skin tumor development in SKH-1 hairless mice. Likewise, dietary rosiglitazone did not statistically significantly inhibit DMBA/TPA-induced skin tumor development. Interestingly, dietary troglitazone significantly inhibited basal level keratinocyte proliferation as shown by 5-bromo-2'-deoxyuridine (BrdU) labeling, but it had no effect on TPA-induced epidermal cell proliferation. Northern blot analysis showed that PPARgamma expression was extremely low in normal mouse epidermis and was virtually undetectable in skin tumors. Collectively, our data suggest that PPARgamma ligands may not be useful in the prevention of chemically or UV-induced skin tumors.
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PMID:The effect of PPARgamma ligands on UV- or chemically-induced carcinogenesis in mouse skin. 1586 2

Overexpression of human epidermal growth factor receptor 2 (HER-2/neu) characterizes a molecular subtype of breast cancer associated with poor clinical outcome. Preventive strategies for HER-2/neu-positive breast cancer, which is often estrogen and progesterone receptor negative, remain undefined. Activators of peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor also expressed in breast cancer, hold potential as cancer prevention agents. PPARgamma ligands include specific fatty acids and synthetic compounds, such as the thiazolidinediones, which appear to inhibit cell proliferation and tumorigenesis. We hypothesized that a thiazolidinedione, rosiglitazone, may serve as a chemopreventive agent for HER-2/neu-associated mammary carcinogenesis, but that efficacy may be influenced by dietary fat content. We studied the effects of diets enriched with corn or fish oil (25% of energy) with and without rosiglitazone (12 g/kg) in a 2 x 2 factorial design on mammary tumorigenesis in murine mammary tumor virus (MMTV)-HER-2/neu transgenic mice. Despite in vitro evidence of antiproliferative effects in an MMTV-HER-2/neu tumor cell line, rosiglitazone did not affect mammary carcinogenesis in vivo. Interestingly, fish oil-based diets markedly suppressed breast tumor incidence (57% of mice vs. 87% of corn oil-fed mice, P = 0.0001) as well as tumor multiplicity (P = 0.001) and mammary gland dysplasia (P = 0.001). These findings demonstrate a potent preventive effect of (n-3) PUFA on HER-2/neu-mediated mammary carcinogenesis, without interaction with a synthetic PPARgamma activator. Further studies focusing on the mechanisms by which (n-3) fatty acids suppress HER-2/neu signaling pathways involved in the pathogenesis of breast cancer are warranted.
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PMID:Dietary (n-3) polyunsaturated fatty acids inhibit HER-2/neu-induced breast cancer in mice independently of the PPARgamma ligand rosiglitazone. 1586 69

Cyclooxygenases (Cox) are prostaglandin synthetase enzymes which play a key role in mammary carcinogenesis. Several connections were demonstrated between Cox and a few oncogenes (v-src, v-Ha-ras, HER-2\neu, Wnt, p53 mutated), alimentary products (PUFAs), transcription factors (c-jun and c-fos), proapoptotic proteins [Bax et Bcl-x(L)] or antiapoptotic (Bcl-2), CYP19 aromatase gene, NFkappaB receptor (RANKL), angiogenesis (via VEGF, TXA2, oxid nitric synthetase, alphaVbeta3 integrin receptor), peroxisome gamma proliferator receptor (PPARgamma) and its ligand PGJ2 and with antitubuline chemotherapy drugs. No correlation of Cox2 expression with hormonal receptors was shown. In epidemiologic studies there is evidence of breast cancer risk reduction for women who take AINS for a lon time. Alimentary factors like resveratrol or insaturated fat acid reduce Cox2 expression in animal and could be investigated in human studies. Clinical trials are planed with the anti Cox2 celecoxib for breast cancer prevention, in adjuvant setting, in metastatic situation combined with exemestane or antitubulin drugs or in neoadjuvant therapy.
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PMID:[Cyclooxygenase 2 and breast cancer. From biological concepts to clinical trials]. 1589 33

Multifaceted evidence links the development of liver tumours to the activation and proliferation of adult liver progenitor (oval) cells during the early stages of chronic liver injury. The aim of this study was to examine the role of the peroxisome proliferator activated receptors (PPARs): PPARalpha, delta and gamma, in mediating the behaviour of liver progenitor cells during pre-neoplastic disease and to investigate their potential as therapeutic targets for the treatment of chronic liver injury. We observed increased liver expression of PPARalpha and gamma in concert with expanding oval cell numbers during the first 21 days following commencement of the choline deficient, ethionine supplemented (CDE) dietary model of carcinogenic liver injury in mice. Both primary and immortalized liver progenitor cells were found to express PPARalpha, delta and gamma, but not gamma2, the alternate splice form of PPARgamma. WY14643 (PPARalpha agonist), GW501516 (PPARdelta agonist) and ciglitazone (PPARgamma agonist) were tested for their ability to modulate the behaviour of p53-immortalized liver (PIL) progenitor cell lines in vitro. Both PPARdelta and gamma agonists induced dose-dependent growth inhibition and apoptosis of PIL cells. In contrast, the PPARalpha agonist had no effect on PIL cell growth. None of the drugs affected the maturation of PIL cells along either the hepatocytic or biliary lineages, as judged by their patterns of hepatic gene expression prior to and following treatment. Administration of the PPARgamma agonist ciglitazone to mice fed with the CDE diet for 14 days resulted in a significantly diminished oval cell response and decreased fibrosis compared with those receiving placebo. In contrast, GW501516 did not affect oval cell numbers or liver fibrosis, but inhibited CDE-induced hepatic steatosis. In summary, PPARgamma agonists reduce oval cell proliferation and fibrosis during chronic liver injury and may be useful in the prevention of hepatocellular carcinoma.
Carcinogenesis 2005 Oct
PMID:Inhibition of adult liver progenitor (oval) cell growth and viability by an agonist of the peroxisome proliferator activated receptor (PPAR) family member gamma, but not alpha or delta. 1591 8

Peroxisome proliferator-activated receptor gamma (PPARgamma) is known to be expressed in several cancers, and the treatment of these cancer cells with PPARgamma ligands often induces cell differentiation and apoptosis. Recently, the chemopreventive potential of PPARgamma ligands on colon carcinogenesis was reported, although the effect of PPARgamma on colon carcinogenesis and the mechanism of the effect remain controversial. In this study, we attempted to elucidate the role of PPARgamma in gastric carcinogenesis and explored the possible use of PPARgamma ligand as a chemopreventive agent for gastric cancer. N-methyl-N-nitrosourea (MNU, 240 ppm) was given in drinking water for 10 weeks to induce gastric cancer in PPARgamma wild-type (+/+) and heterozygous-deficient (+/-) mice, followed by treatment with PPARgamma ligand [troglitazone, 0.15% (w/w) in powder food] or the vehicle alone for 42 weeks. At the end of the experiment, PPARgamma (+/-) mice were more susceptible to MNU-induced gastric cancer than wild-type (+/+) mice (89.5%/55.5%), and troglitazone significantly reduced the incidence of gastric cancer in PPARgamma (+/+) mice (treatment 55.5%/vehicle 9%) but not in PPARgamma (+/-) mice. The present study showed that (a) PPARgamma suppresses gastric carcinogenesis, (b) the PPARgamma ligand troglitazone is a potential chemopreventive agent for gastric carcinogenesis, and (c) troglitazone's chemopreventive effect is dependent on PPARgamma.
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PMID:Chemopreventive effect of peroxisome proliferator-activated receptor gamma on gastric carcinogenesis in mice. 1593 Feb 96

Conjugated linoleic acid (CLA) has been shown to exert beneficial effects against carcinogenesis, atherosclerosis and diabetes. It has been demonstrated that CLA modulates lipid metabolism through the activation of peroxisome proliferator-activated receptors (PPARs). The PPAR family comprises 3 closely related gene products, PPAR alpha, beta/delta and gamma, differing for tissue distribution, developmental expression and ligand specificity. It has also been demonstrated that activated PPARgamma results in growth inhibition and differentiation of transformed cells. These observations stimulated a great interest toward PPARgamma ligands as potential anticancer drugs to be used in a differentiation therapy. Glioblastomas are the most commonly diagnosed primary tumors of the brain in humans. The prognosis of patients with high-grade gliomas is poor and only marginally improved by chemotherapy. The aim of this work was to study the effects of CLA and of a specific synthetic PPARgamma ligand on cell growth, differentiation and death of a human glioblastoma cell line as well as on parameters responsible for the metastatic behavior of this tumor. We demonstrate here that CLA and PPARgamma agonist strongly inhibit cell growth and proliferation rate and induce apoptosis. Moreover, both treatments decrease cell migration and invasiveness. The results obtained show that CLA acts, directly or indirectly, as a PPARgamma activator, strongly suggesting that this naturally occurring fatty acid may be used as brain antitumor drug and as a chemopreventive agent. Moreover, the gamma-agonist, once experimented and validated on man, may represent a useful coadjuvant in glioblastoma therapy and in the prevention of recurrences.
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PMID:PPARgamma-dependent effects of conjugated linoleic acid on the human glioblastoma cell line (ADF). 1598 37

Stromal-epithelial interactions and the bioactive molecules produced by these interactions maintain tissue homeostasis and influence carcinogenesis. Bioactive prostaglandins produced by prostaglandin synthases and secreted by the prostate into seminal plasma are thought to support reproduction, but their endogenous effects on cancer formation remain unresolved. No studies to date have examined prostaglandin enzyme production or prostaglandin metabolism in normal prostate stromal cells. Our results show that lipocalin-type prostaglandin D synthase (L-PGDS) and prostaglandin D2 (PGD2) metabolites produced by normal prostate stromal cells inhibited tumor cell growth through a peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent mechanism. Enzymatic products of stromal cell L-PGDS included high levels of PGD2 and 15-deoxy-delta(12,14)-PGD2 but low levels of 15-deoxy-delta(12,14)-prostaglandin J2. These PGD2 metabolites activated the PPARgamma ligand-binding domain and the peroxisome proliferator response element reporter systems. Thus, growth suppression of PPARgamma-expressing tumor cells by PGD2 metabolites in the prostate microenvironment is likely to be an endogenous mechanism involved in tumor suppression that potentially contributes to the indolence and long latency period of this disease.
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PMID:Suppression of prostate tumor cell growth by stromal cell prostaglandin D synthase-derived products. 1602 20


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