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)

Human colon cancer is associated with antigenic and structural changes in mucin-type carbohydrate chains (O-glycans). To elucidate the control of the biosynthesis of these O-glycans is colon cancer, we have studied glycosyltransferase and sulphotransferase activities involved in the assembly of elongated O-glycan structures. We analysed homogenates prepared from cancer tissue, adjacent normal and distal normal tissue from 20 patients. Several transferase activities showed pronounced changes in cancer tissue. The changes correlate with previous findings of a loss of O-glycans in cancer mucins, but did not always correlate with levels of Tn, sialyl-Tn, T and Lex antigens in homogenates or with the differentiation status and Duke's stages of the cancer tissue or the patient's blood type, sex and age. UDP-GlcNAc: Gal NAc-R beta 3-N-acetylglucosaminyltransferase (where GlcNAc is N-acetyl-D-glucosamine and GalNAc is N-acetyl-D-galactosamine) synthesizing O-glycan core 3, GlcNAc beta 1-3GalNAc-, CMP-sialic acid: GalNAc-peptide alpha 6-sialyltransferase synthesizing the sialyl-Tn antigen and sulphotransferase activities towards O-glycan core 1, Gal beta 1-3GalNAc-, were found to be decreased in cancer. UDP-GlcNAc: Gal beta 1-3GalNAc beta 6-N-acetylglucosaminyltransferase was also decreased in cancer concomitant with a loss of the ability to synthesize the I antigen and core 4, GlcNAc beta 1-6(GlcNAc beta 1-3) GalNAc-, CMP-sialic acid: Gal beta 1-3GalNAc-R alpha 3-sialyltransferase and GDP-fucose: Gal beta-R alpha 2-fucosyltransferase, synthesizing the blood group H determinant, were found to be 4- and 3- to 8-fold increased, respectively, in cancer compared to normal tissue. The data suggest that the biosynthesis of antigens and mucin-bound O-glycan structures in colon cancer is subject to complex control mechanisms.
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PMID:Alterations of O-glycan biosynthesis in human colon cancer tissues. 773 50

Recent results have shown that autophagic sequestration in the human colon cancer cell line HT-29 is controlled by the pertussis toxin-sensitive heterotrimeric Gi3 protein. Here we show that transfection of an antisense oligodeoxynucleotide to the alphai3-subunit markedly inhibits autophagic sequestration, whereas transfection of an antisense oligodeoxynucleotide to the alphai2-subunit does not change the rate of autophagy in HT-29 cells. Autophagic sequestration was arrested in cells transfected with a mutant of the alphai3-subunit (Q204L) that is restricted to the GTP-bound form. In Q204L-expressing cells, 3-methyladenine-sensitive degradation of long lived [14C]valine-labeled proteins was severely impaired and could not be stimulated by nutrient deprivation. Autophagy was also reduced when dissociation of the betagamma dimer from the GTP-bound alphai3-subunit was impaired in cells transfected with the G203A mutant. In contrast, a high rate of pertussis toxin-sensitive autophagy was observed in cells transfected with an alphai3-subunit mutant (S47N) which has an increased guanine nucleotide exchange rate and increased preference for GDP over GTP. Cells that express pertussis toxin-insensitive mutants of either wild-type alphai3-subunit (C351S) or S47N alphai3-subunit (S47N/C351S) exhibit a high rate of autophagy.
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PMID:Guanine nucleotide exchange on heterotrimeric Gi3 protein controls autophagic sequestration in HT-29 cells. 891 Apr 89

AGS3 contains GoLoco or G-protein regulatory motifs in its COOH-terminal half that stabilize the GDP-bound conformation of the alpha-subunit of the trimeric Gi3 protein. The latter is part of a signaling pathway that controls the lysosomal-autophagic catabolism in human colon cancer HT-29 cells. In the present work we show that the mRNA encoding for AGS3 is expressed in human intestinal cell lines (Caco-2 and HT-29) whatever their state of differentiation. Together with the full-length form, minute amounts of the mRNA encoding a NH2-terminal truncated form of AGS3, previously characterized in cardiac tissues, were also detected. Both the endogenous form of AGS3 and a tagged expressed form have a localization compatible with a role in the Galphai3-dependent control of autophagy. Accordingly, expressing its non-Galphai3-interacting NH2-terminal domain or its Galphai3-interacting COOH-terminal domain reversed the stimulatory role of AGS3 on autophagy. On the basis of biochemical and morphometric analysis, we conclude that AGS3 is involved in an early event during the autophagic pathway probably prior to the formation of the autophagosome. These data demonstrate that AGS3 is a novel partner of the Galphai3 protein in the control of a major catabolic pathway.
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PMID:The G-protein regulator AGS3 controls an early event during macroautophagy in human intestinal HT-29 cells. 1264 77

K-ras mutations occur frequently in colon cancer and contribute to autonomous growth. In the azoxymethane (AOM) model of colon cancer, in addition to K-ras mutations, we have shown that wild-type (WT) Ras can be activated by upstream pathways, including, e.g., signaling by ErbB receptors. Tumors with mutant or activated WT Ras had increased cyclooxygenase-2 (Cox-2) expression. We have also shown that ursodeoxycholic acid (UDCA) prevented AOM-induced colon cancer and suppressed Cox-2 induction. In this study, we examined the role of Ras in Cox-2 inhibition by UDCA. Rats were fed AIN-76A chow alone, or supplemented with 0.4% UDCA, and received 20 mg/kg AOM i.p. weekly x 2 weeks. At 40 weeks, rats were sacrificed, and tumors were harvested. K-ras mutations were assessed by primer-mediated RFLP, allele-specific oligonucleotide hybridization, and direct DNA sequencing. Ras was immunoprecipitated and defined as activated if [Ras - GTP/(Ras - GTP + Ras - GDP)] was >3 SD above normal colonocytes. Cox-2 mRNA was determined by reverse transcription-PCR, and protein expression was assessed by Western blotting and immunostaining. In the AOM alone group, Ras was activated by mutations in 8 of 30 (27%) tumors, and WT Ras was activated in 7 of 30 (23%) tumors. UDCA significantly suppressed the incidence of tumors with mutant Ras (1 of 31, 3.2%; P < 0.05) and totally abolished the development of tumors with activated WT Ras (0 of 10; P < 0.05). In the AOM alone group, Cox-2 was up-regulated >50-fold in tumors with normal Ras activity and further enhanced in tumors with mutant or signaling-activated Ras. UDCA significantly inhibited Cox-2 protein and mRNA levels in tumors with normal Ras activity. In summary, we have shown for the first time that UDCA suppressed the development of tumors with Ras mutations and blocked activation of WT Ras. Furthermore, UDCA inhibited Cox-2 induction by Ras-dependent and -independent mechanisms.
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PMID:Ursodeoxycholic acid inhibits Ras mutations, wild-type Ras activation, and cyclooxygenase-2 expression in colon cancer. 1283 36

Macroautophagy or autophagy is an ubiquitous and conserved degradative pathway of cytosolic components, macromolecules or organelles, into the lysosome. By using biochemical and microscopic methods, which allow one to measure the rate of autophagy, the role of two regulators of Gi3 protein activity, activator of G-protein-signaling-3 (AGS3) and Galpha-interacting protein (GAIP), was studied in the control of autophagy in human colon cancer HT-29 cells. In HT-29 cells, autophagy is under the control of the Gi3 protein and, when bound to the GTP, the Galphai3 protein inhibits autophagy, whereas it stimulates autophagy when bound to the GDP. GAIP, which enhances the intrinsic GTPase-activating protein activity of the Galphai3 protein, stimulates autophagy by favoring the GDP-bound form of Galphai3. We showed that GAIP is phosphorylated on its serine 151 and that this phosphorylation is dependent on the presence of amino acids that modulate Raf-1 activity, the kinase upstream of Erk1/2. AGS3, a guanine nucleotide dissociation inhibitor, stimulates autophagy by binding Galphai3 proteins. The intracellular localization of AGS3 (Golgi apparatus and endoplasmic reticulum, two membranes known to be at the origin of autophagosomes) is consistent with its role in autophagy.
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PMID:Analyses of Galpha-interacting protein and activator of G-protein-signaling-3 functions in macroautophagy. 1548 68

Inflammatory bowel diseases are associated with increased risk of developing colon cancer. A possible role of the pro-inflammatory leukotriene D4 (LTD4) in this process has been implicated by the findings that LTD4 can signal increased proliferation and survival, both hallmarks of a cancer cell, in non-transformed intestinal epithelial cells. Here we make the novel finding that LTD4 can also signal increased motility in these cells. In parallel, we found that LTD4 induced a simultaneous transient 10-fold increase in Rac but not Cdc42 activity. These data were also supported by the ability of LTD4 to activate the Rac GDP/GTP exchange factor Vav2. Further, LTD4 triggered a 3-fold transient increase in phosphatidylinositol 3-kinase (PI3K) phosphorylation, a possible upstream activator of the Vav2/Rac signaling pathway. The activation of Rac was blocked by the PI3K inhibitors LY294002 and wortmannin and by transfection of a kinase-negative mutant of PI3K or a dominant-negative form of Vav2. Furthermore, Rac was found to co-localize with actin in LTD4-generated membrane ruffles that were formed by a PI3K-dependent mechanism. In accordance, the inhibition of the PI3K and Rac signaling pathway also blocked the LTD4-induced migration of the intestinal cells. The present data reveal that an inflammatory mediator such as LTD4 cannot only increase proliferation and survival of non-transformed intestinal epithelial cells but also, via a PI3K/Rac signaling pathway, trigger a motile response in such cells. These data demonstrate the capacity of inflammatory mediators to participate in the process by which inflammatory bowel conditions increase the risk for colon cancer development.
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PMID:The pro-inflammatory mediator leukotriene D4 induces phosphatidylinositol 3-kinase and Rac-dependent migration of intestinal epithelial cells. 1565 50

The sodium-selective amiloride-sensitive epithelial sodium channel (ENaC) mediates electrogenic sodium re-absorption in tight epithelia. ENaC expression at the plasma membrane requires regulated transport, processing, and macromolecular assembly of subunit proteins in a defined and highly compartmentalized manner. Ras-related Rab GTPases monitor these processes in a highly regulated sequence of events. In order to evaluate the role of Rab proteins in ENaC function, Rab4 wild-type (WT), the GTPase-deficient mutant Rab4Q67L, and the dominant negative GDP-locked mutant Rab4S22N were over-expressed in the colon cancer cell line, HT-29 and amiloride-sensitive currents were recorded. Rab4 over-expression inhibited amiloride-sensitive currents. The effect was reversed by introducing Rab4-neutralizing antibody and Rab4 specific SiRNA. The GDP-locked Rab4 mutant inhibited, while GTPase-deficient mutant moderately stimulated amiloride-sensitive currents. Active status of Rab4 was confirmed by GTP overlay assay, while its expression was verified by Western blotting. Immunoprecipitation and pull-down assay suggest protein-protein interaction between Rab4 and ENaC. In addition, the functional modulation coincides with concomitant changes in ENaC expression at the cell surface and in intracellular pool. We propose that Rab4 is a critical element that regulates ENaC function by mechanisms that include GTP-GDP status, recycling, and expression level. Our observations imply that channel expression in apical membranes of epithelial cell system incorporates RabGTPase as an essential determinant of channel function and adds an exciting paradigm to ENaC therapeutics.
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PMID:Rab4 GTP/GDP modulates amiloride-sensitive sodium channel (ENaC) function in colonic epithelia. 1638 71

Aberrant crypt foci (ACF) are collections of abnormal colonic crypts with heterogeneous molecular and pathologic characteristics. Large and dysplastic ACF are putative precursors of colon cancer with neoplastic risk related to increased proliferation. In this study, we examined the role of epidermal growth factor receptor (EGFR) signaling in regulating ACF proliferation. Using magnification chromoendoscopy, we collected large ACF with endoscopic features of dysplasia and separately biopsied adjacent mucosa. Transcript levels were measured by real-time PCR, proteins were assessed by Western blotting, and levels were expressed as fold changes of adjacent mucosa. K-ras and B-Raf mutations were assessed by PCR and Ras activation by the ratio Ras-GTP / (Ras-GTP + Ras-GDP). At the RNA level, 38% of ACF were hyperproliferative, with proliferating cell nuclear antigen (PCNA) mRNA >/=2-fold of adjacent mucosa. Hyperproliferative ACF had significantly increased mRNA levels of EGFR (6.0 +/- 1.7-fold), transforming growth factor-alpha (14.4 +/- 5.0-fold), heparin-binding EGF-like growth factor (4.5 +/- 1.4-fold), cyclin D1 (4.6 +/- 0.7-fold), and cyclooxygenase-2 (COX-2; 9.3 +/- 4.2-fold; P < 0.05). At the protein level, 46% of ACF were hyperproliferative (PCNA, 3.2 +/- 1.2-fold). In hyperproliferative ACF, 44% possessed significant increases in four EGFR signaling components: EGFR (9.5 +/- 1.3-fold), phosphoactive ErbB2 (2.6 +/- 0.4-fold), phosphoactive extracellular signal-regulated kinase (3.7 +/- 1.1-fold), and cyclin D1 (3.4 +/- 0.8-fold; P < 0.05). Ras was activated in 46% of ACF (3.2 +/- 0.4-fold; P < 0.05), but K-ras mutations were present in only 7% of ACF. In contrast to COX-2 mRNA, the protein was not increased in hyperproliferative ACF. In summary, we have shown that ACF with up-regulated PCNA possess increased EGFR signaling components that likely contribute to the enhanced proliferative state of dysplastic-appearing ACF.
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PMID:Epidermal growth factor receptor signaling is up-regulated in human colonic aberrant crypt foci. 1674 Jul 3

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis through binding to TRAIL receptors, death receptor 4 (DR4), and DR5. TRAIL has potential therapeutic value against cancer because of its selective cytotoxic effects on several transformed cell types. Fucosylation of proteins and lipids on the cell surface is a very important posttranslational modification that is involved in many cellular events. Recently, we found that a deficiency in GDP-mannose-4,6-dehydratase (GMDS) rendered colon cancer cells resistant to TRAIL-induced apoptosis, resulting in tumor development and metastasis by escape from tumor immune surveillance. GMDS is an indispensable regulator of cellular fucosylation. In this study, we investigated the molecular mechanism of inhibition of TRAIL signaling by GMDS deficiency. DR4, but not DR5, was found to be fucosylated; however, GMDS deficiency inhibited both DR4- and DR5-mediated apoptosis despite the absence of fucosylation on DR5. In addition, GMDS deficiency also inhibited CD95-mediated apoptosis but not the intrinsic apoptosis pathway induced by anti-cancer drugs. Binding of TRAIL and CD95 ligand to their cognate receptors primarily leads to formation of a complex comprising the receptor, FADD, and caspase-8, referred to as the death-inducing signaling complex (DISC). GMDS deficiency did not affect formation of the primary DISC or recruitment to and activation of caspase-8 on the DISC. However, formation of secondary FADD-dependent complex II, comprising caspase-8 and cFLIP, was significantly inhibited by GMDS deficiency. These results indicate that GMDS regulates the formation of secondary complex II from the primary DISC independent of direct fucosylation of death receptors.
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PMID:GDP-mannose-4,6-dehydratase (GMDS) deficiency renders colon cancer cells resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor- and CD95-mediated apoptosis by inhibiting complex II formation. 2202 35

Fucosylation is a crucial oligosaccharide modification in cancer. The known function of fucosylation in cancer is to mediate metastasis through selectin ligand-dependent processes. Previously, we found complete loss of fucosylation in the colon cancer cell line HCT116 due to a mutation in the GDP-fucose synthetic enzyme, GDP-mannose-4,6-dehydratase (GMDS). Loss of fucosylation led to escape of cancer cells from tumor immune surveillance followed by tumor progression and metastasis, suggesting a novel function of fucosylation in tumor progression pathway. In the present study, we investigated the frequency of GMDS mutation in a number of clinical colorectal cancer tissue samples: 81 samples of primary colorectal cancer tissue and 39 samples of metastatic lesion including liver and lymph node. Four types of deletion mutation in GMDS were identified in original cancer tissues as well as metastatic lesions. The frequency of GMDS mutation was slightly higher in metastatic lesions (12.8%, 5/39 samples) than in original cancer tissues (8.6%, 7/81 samples). No mutation of the GMDS gene was observed in normal colon tissues surrounding cancer tissues, suggesting that the mutation is somatic rather than in the germline. Immunohistochemical analysis revealed complete loss of fucosylation in three cases of cancer tissue. All three cases had GMDS mutation. In one of three cases, loss of fucosylation was observed in only metastatic lesion, but not its original colon cancer tissue. These data demonstrate involvement of GMDS mutation in the progression of colorectal cancer.
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PMID:Mutation of GDP-mannose-4,6-dehydratase in colorectal cancer metastasis. 2392 70


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