Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclin-dependent kinase family and has been studied mainly in the differentiation of post-mitotic neurons. The purpose of this study was to determine the presence of cdk5 expression and activity in colon cancer cells and to investigate its role in the regulation of PPARgamma ligand-induced antiproliferation. We observed that cdk5 protein levels and kinase activity were elevated in both HT-29 cells and human tumor tissue in comparison to decreased levels in normal colonic mucosa. To elucidate cdk5's role in PPARgamma ligand-induced antiproliferation of colon cancer cells, HT-29 cells were treated with ciglitazone. A dose- and time-dependent decrease in cell proliferation were observed after ciglitazone exposure, which correlated with a decrease in cdk5 protein expression and kinase activity. Importantly, these ciglitazone-induced antiproliferative changes were reversed when cdk5 was overexpressed. Although present, p35, the regulatory protein of cdk5, showed no significant changes in protein expression with the introduction of ciglitazone. This is the first report of cdk5/p35 expression and kinase activity in colon cancer cells, which is associated with ciglitazone-induced antiproliferation in HT-29 cells.
 ...
PMID:CDK5 is a novel regulatory protein in PPARgamma ligand-induced antiproliferation. 1632 95

The effect on peritoneal metastasis of linoleic acid (LA) was examined using in vitro treatment of cancer cells and mouse peritoneal metastasis models. Firstly, cell growth of MKN28 human gastric cancer cells and Colo320 human colon cancer cells was suppressed by LA in a dose-dependent manner with increment of apoptosis. LA-induced growth inhibition was recovered by the exposure to antisense S-oligodeoxynucleotide for peroxisome proliferator-activated receptor gamma (PPARgamma) or 15-lipoxygenase-1, which converts LA to PPARgamma ligands. LA significantly inhibited invasion into type-IV collagen-coated membrane of MKN28 and Colo320 cells (p<0.05). BALB/c nu/nu mice inoculated with MKN28 and Colo320 cells into their peritoneal cavities were administrated with LA intraperitoneally (weekly, four times). The LA treatment significantly diminished the number of metastatic foci of both cells in the peritoneal cavity (p<0.05). Protein production in MKN28 and Colo320 cells treated with LA showed a decrease of epidermal growth factor receptor and an increase of Bax. These findings suggest that LA inhibits invasion and metastasis of human gastric and colon cancer cells by nondietary administration.
 ...
PMID:Peritoneal metastasis inhibition by linoleic acid with activation of PPARgamma in human gastrointestinal cancer cells. 1636 14

Epidemiologically, a high-fat diet is associated with the risk of colon cancer. In addition, serum levels of triglycerides (TGs) and cholesterol have been demonstrated to be positively associated with colon carcinogenesis. We recently found that an age-dependent hyperlipidemic state (high serum TG levels) exists in Apc-deficient mice, an animal model for human familial adenomatous polyposis. The mRNA levels of lipoprotein lipase (LPL), which catalyzes TG hydrolysis, were shown to be downregulated in the liver and intestines of mice. Moreover, treatment with a peroxisome proliferator-activated receptor (PPAR) alpha agonist, bezafibrate, or a PPARgamma agonist, pioglitazone, suppressed both hyperlipidemia and intestinal polyp formation in the mice, with induction of LPL mRNA. PPARalpha and PPARgamma agonists are reported to exert anti-proliferative and pro-apoptotic effects in cancer cells. One compound that also increases LPL expression levels but does not possess PPAR agnostic activity is NO-1886. When given at 400 or 800 ppm in the diet, it suppresses both hyperlipidemia and intestinal polyp formation in Apc-deficient mice, with elevation of LPL mRNA. In conclusion, a decrease in serum lipid levels by increasing LPL activity may contribute to a reduction in intestinal polyp formation with Apc deficiency. PPARalpha and PPARgamma agonists, as well as NO-1886, could be useful as chemopreventive agents for colon cancer.
 ...
PMID:Concomitant suppression of hyperlipidemia and intestinal polyp formation by increasing lipoprotein lipase activity in Apc-deficient mice. 1660 35

Probiotics have been shown to reduce the incidence of colon cancer in animal models. The mechanisms responsible for this activity are poorly defined. Conjugated linoleic acids (CLA) are a group of isomers of linoleic acid (LA) possessing anti-inflammatory and anticarcinogenic properties, which can be produced from LA by certain bacterial strains. In this study, the ability of probiotic bacteria to exert anticarcinogenic effects through the production of CLA was assessed. Incubation of probiotic bacteria (VSL3, Lactobacillus acidophilus, L. bulgaricus, L. casei, L. plantarum, Bifidobacterium breve, B. infantis, B. longum, and Streptococcus thermophilus) in the presence of LA yielded CLA production as measured by gas chromatography. Conditioned medium, containing probiotic-produced CLA, reduced viability and induced apoptosis of HT-29 and Caco-2 cells, as assessed by MTT assay and DNA laddering, respectively. Western blotting demonstrated an increased expression of PPARgamma in cells treated with conditioned medium compared with LA alone. Incubation of murine feces with LA after administering VSL3 yielded 100-fold more CLA than feces collected prior to VSL3 feeding. This study supports a role for supplemental probiotics as a strategy both for attenuating inflammation and for preventing colon cancer.
 ...
PMID:Bioproduction of conjugated linoleic acid by probiotic bacteria occurs in vitro and in vivo in mice. 1670 8

1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing p-trifluoromethyl, t-butyl, and phenyl [1,1-bis(3'-indolyl)-1-(p-phenyl)methane (DIM-C-pPhC(6)H(5))] substituents induce peroxisome proliferator-activated receptor gamma (PPARgamma)-mediated transactivation in SW480 colon cancer cells. These PPARgamma-active compounds also inhibit cell proliferation and modulate some cell cycle proteins. At concentrations from 2.5 to 7.5 micromol/L, the PPARgamma agonists induce caveolin-1 and phosphorylation of Akt and cotreatment with the PPARgamma antagonist GW9662 inhibited the induction response. In contrast, higher concentrations (10 micromol/L) of 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing 1,1-bis(3'-indolyl)-1-(p-trifluoromethyl)methane and DIM-C-pPhC(6)H(5) induce apoptosis, which is PPARgamma independent. This was accompanied by loss of caveolin-1 induction but induction of proapoptotic nonsteroidal anti-inflammatory drug activated gene-1. In athymic nude mice bearing SW480 cell xenografts, DIM-C-pPhC(6)H(5) inhibits tumor growth at doses of 20 and 40 mg/kg/d and immunohistochemical staining of the tumors showed induction of apoptosis and nonsteroidal anti-inflammatory drug activated gene-1 expression. Thus, the indole-derived PPARgamma-active compounds induce both receptor-dependent and receptor-independent responses in SW480 cells, which are separable over a narrow range of concentrations. This dual mechanism of action enhances their antiproliferative and anticancer activities.
 ...
PMID:1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through PPARgamma-dependent and PPARgamma-independent pathways. 1673 70

Previous results indicate that the polyphenol resveratrol inhibits cell growth of colon carcinoma cells via modulation of polyamine metabolic key enzymes. The aim of this work was to specify the underlying molecular mechanisms and to identify a possible role of transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma). Cell growth was determined by bromodeoxyuridine incorporation and crystal violet staining. Protein levels were examined by Western blot analysis. Spermine/spermidine acetyltransferase (SSAT) activity was determined by a radiochemical assay. PPARgamma ligand-dependent transcriptional activity was measured by a luciferase assay. A dominant-negative PPARgamma mutant was transfected in Caco-2 cells to suppress PPARgamma-mediated functions. Resveratrol inhibits cell growth of both Caco-2 and HCT-116 cells in a dose- and time-dependent manner (P < 0.001). In contrast to Caco-2-wild type cells (P < 0.05), resveratrol failed to increase SSAT activity in dominant-negative PPARgamma cells. PPARgamma involvement was further confirmed via ligand-dependent activation (P < 0.01) as well as by induction of cytokeratin 20 (P < 0.001) after resveratrol treatment. Coincubation with SB203580 abolished SSAT activation significantly in Caco-2 (P < 0.05) and HCT-116 (P < 0.01) cells. The involvement of p38 mitogen-activated protein kinase (MAPK) was further confirmed by a resveratrol-mediated phosphorylation of p38 protein in both cell lines. Resveratrol further increased the expression of PPARgamma coactivator PGC-1alpha (P < 0.05) as well as SIRT1 (P < 0.01) in a dose-dependent manner after 24 hours of incubation. Based on our findings, p38 MAPK and transcription factor PPARgamma can be considered as molecular targets of resveratrol in the regulation of cell proliferation and SSAT activity, respectively, in a cell culture model of colon cancer.
 ...
PMID:Peroxisome proliferator-activated receptor gamma as a molecular target of resveratrol-induced modulation of polyamine metabolism. 1684 86

Multiple investigations of the effects of peroxisome proliferator-activated receptor gamma (PPARgamma) ligands on colon cancer have produced contradictory results. While some studies demonstrated increased numbers of colonic polyps in Apc(Min/+) mice treated with various thiazolidinedione (TZD) PPARgamma ligands, others reported amelioration of tumor multiplicity and progression in both Apc(Min/+) mice and in mice with chemically-induced colon cancer. Here, we addressed the role of PPARgamma in murine intestinal tumorigenesis using gene knockout methodology. We found that either heterozygous or homozygous intestinal-specific PPARgamma deficiency enhanced the number of Apc(Min/+) tumors in both the small intestine and colon, especially in the colon, where PPARgamma deficiency also modulated tumor incidence. Gender significantly affected tumor multiplicity independent of PPARgamma genotype. Female Apc(Min/+) mice developed more tumors in the small intestine and more tumors overall, whereas male Apc(Min/+) mice developed more tumors in the colon. Nevertheless, intestinal PPARgamma deficiency enhanced tumorigenesis irrespective of gender. Our results suggest that PPARgamma functions as a tumor resistance factor in the mouse intestine and warrant further investigation of the PPARgamma-dependent and independent actions of TZDs in cancer.
 ...
PMID:Intestinal-specific PPARgamma deficiency enhances tumorigenesis in ApcMin/+ mice. 1685 78

PPAR involvement in cell growth was investigated "in vivo" and "in vitro" and was correlated with cell proliferation and apoptotic death. "In vivo" PPARgamma and alpha were evaluated in colon cancer specimens and adjacent nonneoplastic colonic mucosa. PPARgamma increased in most cancer specimens versus mucosa, with a decrease in c-Myc and in PCNA proteins, suggesting that colon cancer growth is due to increased cell survival rather than increased proliferation. The prevalence of survival over proliferation was confirmed by Bcl-2 or Bcl-X(L) increase in cancer versus mucosa, and by decreased PPARalpha. "In vitro" PPARgamma and PPARalpha were evaluated in human tumor and normal cell lines, treated with natural or synthetic ligands. PPARgamma was involved in inhibiting cell proliferation with a decrease in c-Myc protein, whereas PPARalpha was involved in inducing apoptosis with modulation of Bcl-2 and Bad proteins. This involvement was confirmed using specific antagonists of two PPARs. Moreover, the results obtained on treating cell lines with PPAR ligands confirm observations in colon cancer: there is an inverse correlation between PPARalpha and Bcl-2 and between PPARgamma and c-Myc.
 ...
PMID:Involvement of PPARs in Cell Proliferation and Apoptosis in Human Colon Cancer Specimens and in Normal and Cancer Cell Lines. 1738 73

Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a ligand-activated transcription factor, is a key regulator of adipogenic differentiation and glucose homeostasis. PPAR-gamma ligands have recently been demonstrated to affect proliferation and differentiation in cancer cells lines. The aim of the present work was to examine PPAR-gamma expression in colon cancer cases. PPAR-gamma expression was examined immunohistochemically in 86 colon cancer cases and was correlated with clinicopathological parameters, tumor proliferative capacity, cell cycle-related molecule expression, and patient survival. Positive PPAR-gamma immunostaining was prominent in 48 of 86 cases (56%). PPAR-gamma positivity was not correlated with Dukes' stage, histological grade of differentiation, lymph node and liver metastasis, venous invasion, tumor proliferative capacity, or patient survival. A statistically significant correlation was found between PPAR-gamma and the expression of cell cycle-related molecules pRb (P < 0.016), cyclin D1 (P <0.009), p16 (P<0.032), and p21 (P<0.033), while a positive trend for cyclin E was also noted (P<0.057). The pattern, intensity, and extent of PPAR-gamma expression in positive cases were not correlated with any of the examined variables. Our findings support evidence for participation of this protein in the biological mechanisms underlying carcinogenic evolution in the colon, also suggesting the importance of specific PPAR-gamma ligands as cell cycle modulators for a future therapeutic approach in colon cancer.
 ...
PMID:Expression of peroxisome proliferator-activated receptor-gamma in colon cancer: correlation with histopathological parameters, cell cycle-related molecules, and patients' survival. 1871 78

PPARgamma ligands inhibit growth and induce apoptosis of various cancer cells. 4-Hydroxynonenal (HNE), a product of lipid peroxidation, inhibits proliferation and induces differentiation or apoptosis in neoplastic cells. The aim of this work was to investigate the effects of PPARgamma ligands (rosiglitazone and 15-deoxy-prostaglandin J2 (15d-PGJ2)) and HNE, alone or in association, on proliferation, apoptosis, differentiation, and growth-related and apoptosis-related gene expression in colon cancer cells (CaCo-2 cells). PPARgamma ligands inhibited cell proliferation (IC50 was 37.47+/-6.6 microM, for 15d-PGJ2, and 170.34+/-20 microM for rosiglitazone). HNE (1 microM) inhibited cell growth by 70%. Apoptosis was induced by 15d-PGJ2 and HNE and, to a minor extent, rosiglitazone. Differentiation was induced by rosiglitazone and by 15d-PGJ2, but not by HNE. PPARgamma ligands inhibited c-myc expression. HNE induced a transitory increase in c-myc expression and a subsequent down-regulation. HNE induced p21 expression, whereas PPARgamma ligands did not. Expression of the bax gene was increased by HNE and 15d-PGJ2, but not by rosiglitazone. No synergism or antagonism was found between HNE and PPARgamma ligands. Both apoptosis and differentiation induction may be responsible for the inhibition of proliferation by PPARgamma ligands; apoptosis and c-myc and p21 expression seem to be involved in the inhibition of proliferation by HNE.
 ...
PMID:4-Hydroxynonenal and PPARgamma ligands affect proliferation, differentiation, and apoptosis in colon cancer cells. 1746 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>