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 HT-29 cells exhibit a differentiation-dependent autophagic-lysosomal pathway that is responsible for the degradation of a pool of newly synthesized N-linked glycoproteins in undifferentiated cells. In the present study, we have investigated the molecular control of this degradative pathway in undifferentiated HT-29 cells. For this purpose, we have modulated the function and expression of the heterotrimeric G-proteins (Gs and Gi) in these cells. After pertussis toxin treatment which ADP-ribosylates heterotrimeric Gi-proteins, we observed an inhibition of autophagic sequestration and the complete restoration of the passage of N-linked glycoproteins through the Golgi complex. In contrast, autophagic sequestration was not reduced by cholera toxin, which acts on heterotrimeric Gs-proteins. Further insights on the nature of the pertussis toxin-sensitive alpha subunit controlling autophagic sequestration were obtained by cDNA transfections of alpha i subunits. Overexpression of the alpha i3 subunit increased autophagic sequestration and degradation in undifferentiated cells, whereas overexpression of the alpha i2 subunit, the only other pertussis toxin-sensitive alpha subunit expressed in HT-29 cells, did not alter the rate of autophagy.
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PMID:A heterotrimeric Gi3-protein controls autophagic sequestration in the human colon cancer cell line HT-29. 781 64

The correlation between the activation of macrophages by lipopolysaccharides (LPS) from four different bacterial species and their antitumor effect in a rat model of colon cancer was investigated. The efficacy of LPS from Neisseria meningitidis (Nm), Salmonella minnesota (Sm), Escherichia coli (Ec) and Bordetella pertussis (Bp) was evaluated as the smallest concentration inducing rat peritoneal macrophages (pm psi) to produce tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6 and nitric oxide (NO). The cytokine production was measured in bioassays and NO production quantitatively with Griess reactant. Nm was the most effective LPS with concentrations of 1 ng/10(6) pm psi for the induction of TNF, IL-1 and IL-6 activities and 0.01 ng/10(6) pm psi for the induction of NO production. The range between efficacy of different LPS was broad from 1 to 10(4)-10(5) for TNF activity, 1 to 10(2)-10(3) for NO production and IL-6 activity and 1 to 10-10(2) for IL-1 activity. In vivo antitumor effect was evaluated on the growth of peritoneal carcinomatosis. Complete tumor regressions were observed, the LPS rating with respect to decreasing efficacy was Nm, Sm, Ec then Bp; Nm, Sm and Ec were very closed while Bp was not effective. These results show the correlation between the antitumor effect in vivo of LPS and their capacity to induce in vitro IL-1 activity, but not between their ability to induce NO production, TNF and IL-6 activities.
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PMID:Correlation between the capacity to activate macrophages in vitro and the antitumor activity in vivo of lipopolysaccharides from different bacterial species. 808 53

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

The trimeric G(i3) protein-dependent lysosomal-autophagic pathway is responsible for the degradation of a pool of N-linked glycoproteins in the human colon cancer HT-29 cell line. Here we have followed the fate of N-glycans using HT-29 cells either overexpressing the wild-type G alpha(i3) protein or transfected with different mutants of the G alpha(i3) protein. The stabilization of N-glycans was dependent upon the inhibition of autophagic sequestration by either 3-methyladenine (3-MA) or pertussis toxin (PTX). However, PTX allowed the processing of high-mannose glycans whereas 3-MA did not. The destabilization of the Golgi apparatus by brefeldin A, which interrupts the intracellular trafficking of N-linked glycoproteins along the secretory pathway, did not interfere with the macroautophagic pathway. These results suggest that the lysosomal-autophagic pathway is not dependent upon the integrity of the Golgi apparatus and points to differences between the molecular properties of two membrane flow processes (macroautophagy, exocytic pathway) controlled by the trimeric G(i3) protein.
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PMID:Evidence for a dual control of macroautophagic sequestration and intracellular trafficking of N-linked glycoproteins by the trimeric G(i3) protein in HT-29 cells. 919 56

The migration of colonic epithelial cells (restitution) is an important event in the repair of mucosal injuries. Interleukin-8 (IL-8) is a physiological initiator of the chemotactic migration of leucocytes. This study aimed to determine whether IL-8 had a similar effect on migration in an in vitro model of wounded colonic epithelium. Cell migration over 24 h was assessed in circular wounds made in confluent monolayers of the human colon cancer cell line LIM1215. This migration was stimulated in a concentration-dependent manner by IL-8, with maximal effects of approx. 1.75-fold above basal migration. The motogenic effect of IL-8 was mediated independently of effects on cell proliferation. In contrast, it was partially dependent upon gene transcription and protein synthesis and involved the activation of pertussis-toxin-sensitive G-proteins. The short-chain fatty acids, acetate, propionate, butyrate and valerate, the activator of protein kinase C (phorbol-12-myristate-13-acetate) and tumour necrosis factor-alpha (TNF-alpha) all stimulated the secretion of IL-8. However, only the motogenic effect of TNF-alpha was dependent upon IL-8. In conclusion, IL-8 stimulated cell migration in an in vitro model of colonic epithelium, whereas the motogenic effect of at least one physiologically relevant factor was dependent upon an increase in its endogenous levels. If IL-8 stimulates colonic epithelial restitution in vivo, this would have ramifications for the control of repair processes following wounding of the colonic mucosa.
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PMID:Interleukin-8 stimulates the migration of human colonic epithelial cells in vitro. 1046 65

Leukotrienes play an important pathophysiological role in chronic inflammatory states and, as previously shown, cause increased levels of cyclooxygenase-2 (COX-2) in intestinal epithelial cells. The anti-apoptotic protein Bcl-2 is also elevated by LTD(4) stimulation, and in colon cancer, so we studied the mechanisms of COX-2 and Bcl-2 regulation. We found that LTD(4) induced a 3-fold elevation of COX-2 transcription in Int 407 cells and a 2-fold equivalent in colon cancer cells, Caco-2. This was mediated through a pertussis toxin (PTX) sensitive G-protein and the MAP kinase Erk-1/2 pathway, and this was also shown to be the route to up-regulation of Bcl-2 by LTD(4). In good agreement with this, we detected a strong activation of Erk-1/2 that was further increased by COX-2 inhibition, pointing towards the existence of negative feedback regulation. Furthermore, COX-2 activity is responsible for the effects on Bcl-2, but this is not conveyed through the production of PGE(2).
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PMID:Regulation of leukotriene-dependent induction of cyclooxygenase-2 and Bcl-2. 1260 50

Lysophosphatidic acid (LPA) is a mediator of multiple cellular responses. LPA mediates its effects predominantly through the G protein-coupled receptors LPA1, LPA2, and LPA3. In the present work, we studied LPA2-mediated signaling using human colon cancer cell lines, which predominantly express LPA2. LPA2 activated Akt and Erk1/2 in response to LPA. LPA mediated Akt activation was inhibited by pertussis toxin (PTX), whereas Erk1/2 activation was completely inhibited by a blocker of phospholipase Cbeta, U-73122. LPA also induced interleukin-8 (IL-8) synthesis in the colon cancer cells by primarily activating LPA2 receptor. We also found that LPA2 interacts with Na+/H+ exchanger regulatory factor 2 (NHERF2). Activation of Akt and Erk1/2 was significantly attenuated by silencing of NHERF2 expression by RNA interference, suggesting a pivotal role of NHERF2 in LPA2-mediated signaling. We found that expression of LPA2 was elevated, whereas expression of LPA1 downregulated in several types of cancers, including ovarian and colon cancer. We conclude that LPA2 is the major LPA receptor in colon cancer cells and cellular signals by LPA2 are largely mediated through its ability to interact with NHERF2.
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PMID:LPA2 receptor mediates mitogenic signals in human colon cancer cells. 1572 8

Mice deficient in the G-protein alpha subunit G(i)alpha(2) spontaneously develop colitis and colon cancer. IL-11 is a pleiotropic cytokine known to protect the intestinal epithelium from injury in animal models of colitis and is produced by subepithelial myofibroblasts in response to inflammatory mediators including TGF-beta, IL-1beta, and PGE(2). Arachidonic acid release and subsequent PGE(2) production is significantly decreased in the colonic mucosa of G(i)alpha(2)-/- mice, and we hypothesized that this would affect mucosal IL-11 production. Mucosal levels of IL-11 were found to be significantly decreased in G(i)alpha(2)-/- mice despite the presence of mild colitis. Primary cultures of G(i)alpha(2)-/- intestinal and colonic myofibroblasts (IMF and CMF, respectively) produced less basal and TGF-beta or IL-1beta-stimulated IL-11 mRNA and protein than wild-type cells. Inhibitors of ERK or p38 MAPK activation dose dependently inhibited IMF and CMF IL-11 production in response to TGF-beta stimulation, whereas 16,16 dimethyl-PGE(2) and prostanoid receptor subtype-selective agonists induced IL-11 production. Treatment of animals with the EP4-specific agonist ONO-AE1-329 resulted in enhanced mucosal levels of IL-11, and increased IL-11 production by ex vivo cultured CMF. Modulation of cAMP levels produced diverging results, with enhancement of TGF-beta-induced IL-11 release in IMF pretreated with 8-Br-cAMP and inhibition in cells treated either with pertussis toxin or the PKA inhibitor H-89. These data suggest a physiological role for prostaglandins, MAPK signaling, and cAMP signaling for the production of myofibroblast-derived IL-11 in the mouse intestinal mucosa.
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PMID:Decreased MAPK- and PGE2-dependent IL-11 production in Gialpha2-/- colonic myofibroblasts. 1733 78

Lysophosphatidylserine (LPS) can be generated following phosphatidylserine-specific phospholipase A2 activation. The effects of LPS on cellular activities and the identities of its target molecules, however, have not been fully elucidated. In this study, we observed that LPS stimulated intracellular calcium increased in mouse bone marrow-derived mast cells (BMMC), and rat C6 glioma and human HCT116 colon cancer cells and compared the LPS-induced Ca2+ increases with the response by lysophosphatidic acid (LPA), a structurally related bioactive lysolipid. In order to test involvement of signaling molecules in the LPS-induced Ca2+ signaling, we used pertussis toxin (PTX), U73122, and 2-APB, which are specific inhibitors for G proteins, phospholipase C (PLC), and IP3 receptors, respectively. The increases due to LPS and LPA were inhibited by PTX, U-73122 and 2-APB, suggesting that both lipids stimulate calcium signaling via G proteins (Gi/o types), PLC activation, and subsequent IP3 production, although the sensitivity to pharmacological inhibitors varied from complete inhibition to partial inhibition depending on cell type and lysolipid. Furthermore, we observed that Ki16425 completely inhibited an LPS-induced Ca2+ response in three cell types, but that the effect of VPC32183 varied from complete inhibition in BMMC and C6 glioma cells to partial inhibition in HCT116 cells. Therefore, we conclude that LPS increases [Ca2+]i through Ki16425/VPC32183-sensitive G protein-coupled receptors (GPCR), G protein, PLC, and IP3 in mouse BMMC, rat C6, and human HCT116 cells.
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PMID:Lysophosphatidylserine induces calcium signaling through Ki16425/VPC32183-sensitive GPCR in bone marrow-derived mast cells and in C6 glioma and colon cancer cells. 1840 43

Cell migration is critically important in (patho)physiological processes. The metastatic potential of cancer cells partly depends on activation of the coagulation cascade. The aim of the present study was to determine whether coagulation factor X (FXa) can regulate the migration and invasion of cancer cells. Quite unexpectedly, we found that FXa markedly diminished the migration of different cancer cell lines of various origins (breast, lung and colon cancer cells). We showed that FXa mediated inhibition of cancer cell migration was specific, as it was inhibited by TAP (a specific FXa inhibitor) but not by Hirudin (a specific thrombin inhibitor). Moreover, the FXa effect was dose dependent, with a maximal inhibitory effect reached at 0.75 U/ml FXa (corresponding to 130.5 nM). Next, we determined that FXa acted via protease-activated receptor (PAR)-1-dependent signaling, and PAR-1 desensitization, as well as knocking-down PAR-1 expression, abolished the FXa effects. Finally, we showed that Gialpha was not involved in FXa mediated inhibition of cell migration as its effects were not reverted by pertussis toxin. These results suggest that, beyond its role in blood coagulation, FXa plays a key role in cancer cell migration. They also shed light on an unexpected role of PAR-1, which appears to be a Janus-like receptor in cancer cell biology.
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PMID:Coagulation factor Xa inhibits cancer cell migration via protease-activated receptor-1 activation. 1925 Jun 59


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