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

Peroxisome proliferator-activated receptor gamma (PPAR gamma), one of the nuclear receptors expressed in adipose tissue, plays an important role in adipocyte differentiation. In this study, we investigated the expression of PPAR gamma and its role in cellular growth and differentiation in six colon cancer cell lines: HT-29, CaCo-2, SW-480, DLD-1, LoVo, and T-84. All six expressed PPAR gamma mRNA and protein, shown respectively on northern and western blot analyses. Luciferase assay in HT-29 cells, which strongly express PPAR gamma, showed that troglitazone, a selective ligand for PPAR gamma, transactivated the transcription of a peroxisome proliferator response element (PPRE)-driven promoter. Furthermore, troglitazone caused a marked decrease in [3H]thymidine incorporation and G1 cell-cycle arrest determined by flow cytometry. Finally, troglitazone induced expression of mRNAs for villin and intestinal alkaline phosphatase, markers for enterocyte differentiation. In conclusion, human colon cancer cells express PPAR gamma, the ligands of which inhibit cell growth and induce differentiation markers.
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PMID:Peroxisome proliferator-activated receptor gamma induces growth arrest and differentiation markers of human colon cancer cells. 1007 68

The gamma isoform of the peroxisome proliferator-activated receptor, PPAR gamma, regulates adipocyte differentiation and has recently been shown to be expressed in neoplasia of the colon and other tissues. We have found four somatic PPAR gamma mutations among 55 sporadic colon cancers: one nonsense, one frameshift, and two missense mutations. Each greatly impaired the function of the protein. c.472delA results in deletion of the entire ligand binding domain. Q286P and K319X retain a total or partial ligand binding domain but lose the ability to activate transcription through a failure to bind to ligands. R288H showed a normal response to synthetic ligands but greatly decreased transcription and binding when exposed to natural ligands. These data indicate that colon cancer in humans is associated with loss-of-function mutations in PPAR gamma.
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PMID:Loss-of-function mutations in PPAR gamma associated with human colon cancer. 1039 68

The peroxisome proliferator-activated receptor gamma (PPAR gamma) has recently been implicated in the pathogenesis of inflammatory bowel disease (IBD) and colon cancer. The observation that PPAR gamma agonists, through immune modulation, protect against inflammatory processes in the intestine justified their expedient evaluation in the clinical management of IBD. PPAR gamma agonists are reported to have both tumor-promoting and -inhibiting effects in models of colon cancer. These differences can, in part, be explained by PPAR gamma-independent effects of PPAR gamma agonists and by differences in the models used. Because it is still unclear how PPAR gamma impacts on colon cancer, careful monitoring of patients receiving PPAR gamma agonists and additional basic research is indicated before recommendations on the use of PPAR gamma ligands in colon cancer can be made.
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PMID:Nuclear receptors. I. PPAR gamma in the gastrointestinal tract: gain or pain? 1189 16

Troglitazone (TGZ) is a peroxisome proliferator-activated receptor gamma (PPAR gamma) ligand that has pro-apoptotic activity in human colon cancer. Although TGZ binds to PPAR gamma transcription factors as an agonist, emerging evidence suggests that TGZ acts independently of PPAR gamma in many functions, including apoptosis. Early growth response-1 (Egr-1) transcription factor has been linked to apoptosis and shown to be activated by extracellular signal-regulated kinase (ERK). We investigated whether TGZ-induced apoptosis may be related to Egr-1 induction, because TGZ has been known to induce ERK activity. Our results show that Egr-1 is induced dramatically by TGZ but not by other PPAR gamma ligands. TGZ affects Egr-1 induction at least by two mechanisms; TGZ increases Egr-1 promoter activity by 2-fold and prolongs Egr-1 mRNA stability by 3-fold. Inhibition of ERK phosphorylation in HCT-116 cells abolishes the Egr-1 induction by TGZ, suggesting its ERK-dependent manner. Further, the TGZ-induced Egr-1 expression results in increased promoter activity using a reporter system containing four copies of Egr-1 binding sites, and TGZ induces Egr-1 binding activity to Egr-1 consensus sites as assessed by gel shift assay. In addition, TGZ induces ERK-dependent phosphorylation of PPAR gamma, resulting in the down-regulation of PPAR gamma activity. The fact that TGZ-induced apoptosis is accompanied by the biosynthesis of Egr-1 suggests that Egr-1 plays a pivotal role in TGZ-induced apoptosis in HCT-116 cells. Our results suggest that Egr-1 induction is a unique property of TGZ compared with other PPAR gamma ligands and is independent of PPAR gamma activation. Thus, the up-regulation of Egr-1 may provide an explanation for the anti-tumorigenic properties of TGZ.
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PMID:Troglitazone, a peroxisome proliferator-activated receptor gamma (PPAR gamma ) ligand, selectively induces the early growth response-1 gene independently of PPAR gamma. A novel mechanism for its anti-tumorigenic activity. 1247 86

Sulindac, a non-steroidal anti-inflammatory prodrug, is metabolized into pharmacologically active sulfide and sulfone derivatives. Sulindac sulfide, but not sulindac sulfone, inhibits cyclooxygenase (COX) enzyme activities, yet both derivatives have growth inhibitory effects on colon cancer cells. Microarray analysis was used to detect COX-independent effects of sulindac on gene expression in human colorectal cells. Spermidine/sperm-ine N1-acetyltransferase (SSAT) gene, which encodes a polyamine catabolic enzyme, was induced by clinically relevant sulindac sulfone concentrations. Northern blots confirmed increased SSAT RNA levels in these colon cancer cells. Deletion analysis and mutational studies were done to map the sulindac sulfone-dependent response sequences in the SSAT 5'-flanking sequences. This led us to the identification of two peroxisome proliferator-activated receptor (PPAR) response elements (PPREs) in the SSAT gene. PPRE-2, at +48 bases relative to the transcription start site, is required for the induction of SSAT by sulindac sulfone and is specifically bound by PPAR gamma in the Caco-2 cells as shown by transfection and gel shift experiments. PPRE-1, at-323 bases relative to the start site, is not required for the induction of SSAT by sulindac sulfone but can be bound by both PPAR delta and PPAR gamma. Sulindac sulfone reduced cellular polyamine contents in the absence but not in the presence of verapamil, an inhibitor of the export of monoacetyl diamines, inhibited cell proliferation and induced apoptosis. The induced apoptosis could be partially rescued by exogenous putrescine. These data suggest that apoptosis induced by sulindac sulfone is mediated, in part, by the COX-independent, PPAR-dependent transcriptional activation of SSAT, leading to reduced tissue polyamine contents in human colon cancer cells.
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PMID:Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer. 1450 81

In our previous study, a peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist, pioglitazone, suppressed both hyperlipidemia and intestinal polyp formation in Apc(1309) mice at doses of 100 and 200 ppm in the diet. In contrast, it has been reported that doses of 1500 or 2000 ppm of another PPAR gamma agonist, troglitazone, enhanced colon polyp development in Min mice. In the present study, we therefore investigated the effects of a wide range of pioglitazone doses on both hyperlipidemia and intestinal polyp formation in Min mice. Serum triglycerides and very low density lipoprotein (VLDL) cholesterol in the basal diet group were elevated to levels 13-15 times higher than those in the wild-type counterparts at 20 weeks of age. They were reduced dose-dependently by treatment with 100, 200, 400 and 1600 ppm pioglitazone from 6-20 weeks of age with suppression to almost the wild-type level at the highest dose. Moreover, up-regulation of the liver mRNA levels for lipoprotein lipase (LPL) was evident in the pioglitazone-treated animals. Dose-dependent reduction of intestinal polyps was observed in Min mice given 100-1600 ppm for 14 weeks, total numbers being decreased to 63-9% of the control value. A suppressive effect of pioglitazone on colon polyp formation was also found. The PPAR gamma agonist, pioglitazone, may thus be a promising candidate chemopreventive agent for colon cancer.
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PMID:Dose-dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPAR gamma ligand. 1461 72

Epidemiology has revealed that physical activity is an important lifestyle factor that reduces the risk of colon cancer. However, the underlying mechanisms of this protective effect have so far not been defined. The aim of this study was to identify molecular targets of physical activity in rat colon mucosa by employing our voluntary exercise model. Twenty male rats underwent a 12-week exercise program, with 9 additional rats serving as a control group. Running distances, body weights and heart weights as measures of physical adaptations were recorded, and changes in mRNA steady-state levels of marker genes involved in vascularization (VEGF, HIF-1 alpha, ODC-1), apoptosis (Bcl-2, PPAR gamma) and prostaglandin synthesis (COX-2) were determined by qRT-PCR. The four housekeeping genes GAPDH, beta-actin, 18S and ALDA served as reference genes. Recorded running distances showed great inter-individual differences resulting in three different groups of low (L-EX, < 2629 m/night; n=5), moderate (M-EX, 3003 - 7458 m/night; n=10) and high (H-EX, > 8314 m/night; n=5) physical activity. The M-EX and H-EX group revealed significant (p<0.05) adaptive changes with an increase in heart mass per kg body weight and a decrease in mean body weight. Amongst the marker genes studied by mRNA expression analysis only ODC-1 appears to be differentially expressed. Its 1.8-fold increased steady-state mRNA level in the H-EX group suggests that synthesis of polyamines may be increased by physical activity. This new finding could provide a link between extensive physical activity and its protective effects on colon cancer development.
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PMID:Exercise associated genes in rat colon mucosa: upregulation of ornithin decarboxylase-1. 1711 18

Peroxisome proliferator-activated receptor gamma (PPAR gamma) are members of the largest nuclear hormone receptor family of transcription factors (1). PPAR gamma (PPARgamma) plays an important role in adipogenesis, control of sensitivity to insulin, inflammation and atherosclerosis but recent studies also suggest that PPARgamma is involved in cell cycle withdrawal. PPARgamma can promote cell differentiation, exert an antiproliferative action and inhibit angiogenesis (2, 3). However, there are studies showing that activation of PPARgamma promotes the development of colon cancer (4). These data are in sharp contrast with studies that attribute anticancer effects to PPARgamma in gastrointestinal malignancies. Probably, the action of PPARgamma on cell cycle and proliferation depends on the cell type and presence of other stimuli that predispose cells to cancer development. Amidated and non-amidated gastrins may play an important role in the proliferation and carcinogenesis of GI cancers. It is known that gastrin peptides activate phosphorylation of Protein Kinase B (PKB/Akt) and anti-apoptotic signalling but there is little known about the link between gastrins and PPARgamma receptors in relation to apoptosis.
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PMID:Transcriptional upregulation of gastrin in response to peroxisome proliferator-activated receptor gamma agonist triggers cell survival pathways. 1819 88

Ligands for peroxisome proliferator-activated receptor gamma (PPAR gamma) possess anticancer properties. However, the efficacy of PPAR gamma ligands varies in different cancers. In colon cancer, the role of PPAR gamma and its ligands is controversial. We recently showed that downregulation of X-linked inhibitor of apoptosis protein (XIAP) could sensitize colon cancer cells to troglitazone, and 15-deoxy-D12,14-prostaglandin J2 (15-PGJ2) induced cell killing. In our study, we aimed to examine whether rosiglitazone, another more clinically relevant PPAR gamma ligand, has any synergistic anticancer effect with XIAP downregulation in colon cancer. Human colon cancer cell lines HCT116-XIAP(+/+) cells and HCT116-XIAP(-/-) cells were treated with various concentrations of rosiglitazone. The effects of rosiglitazone on cell proliferation, apoptosis and growth of xenograft colon cancers were studied. Rosiglitazone barely suppressed the growth and only very weakly induced apoptosis in HCT116 cells in vitro. Loss of XIAP did not sensitize HCT116 cells to rosiglitazone-induced growth inhibition or apoptosis. In vivo studies revealed that rosiglitazone strongly suppressed the growth of xenograft colon cancer, especially tumors derived from HCT116-XIAP(-/-) cells. The rosiglitazone-treated tumor had reduced expression of ki-67 and lowered mitotic rate. Downregulation of XIAP was associated with an impaired activation of PPAR gamma by its ligand. Rosiglitazone induced marked upregulation of PTEN in HCT116-XIAP(-/-) cells, as well as in xenograft tumors derived from HCT116-XIAP(-/-) cells. We concluded that rosiglitazone significantly suppresses the growth of xenograft colon cancer, and downregulation of XIAP sensitizes the xenograft tumors to rosiglitazone-induced tumor suppression in vivo via upregulation of PTEN.
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PMID:Loss of XIAP sensitizes rosiglitazone-induced growth inhibition of colon cancer in vivo. 1835 48

We investigated whether the anticancer effect of a combination of XIAP down-regulation and PPAR gamma activation on colon cancer is PPARgamma receptor dependent. HCT116-XIAP(+/+) cells and HCT116-XIAP(-/-) cells were treated with troglitazone or 15-deoxy-Delta(12,14)-prostaglandin J2 (15-PGJ2) with or without prior exposure to PPARgamma inhibitor GW9662. Cell proliferation and apoptosis was evaluated. Athymic mice carrying HCT116-XIAP(-/-) cells-derived tumors were treated with troglitazone in the presence or absence of GW9662. Inhibition of cell proliferation and induction of apoptosis by troglitazone and 15-PGJ2 were more prominent in HCT116-XIAP(-/-) cells. PPARgamma ligand-induced growth inhibition, apoptosis, caspase and PARP cleavage could not be blocked by GW9662. Troglitazone significantly retarded growth of xenograft tumors and this effect was not blocked by GW9662. Marked apoptosis and an up-regulation of E-cadherin were observed in xenograft tumor tissues, and GW9662 did not affect these effects. Thus, a combination of XIAP down-regulation and PPARgamma ligands exert a significant anticancer effect in colon cancer via a PPARgamma independent pathway.
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PMID:Loss of XIAP sensitizes colon cancer cells to PPARgamma independent antitumor effects of troglitazone and 15-PGJ2. 1847 1


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