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)

We investigated the effects that phorbol ester and diacylglycerol protein kinase C (PKC) activators had on the chemosensitivity of the human colon cancer cell line KM12L4a to Adriamycin (ADR), vincristine (VCR), and vinblastine (VLB) and on the intracellular accumulation of those drugs. Exposure of the cells to the PKC activator phorbol-12,13-dibutyrate (PDBu) (15 nM) during a 96-hr in vitro chemosensitivity assay significantly reduced the sensitivity of KM12L4a cells to ADR, VCR, and VLB, but not to 5-fluorouracil. Because a 96-hr treatment with 15 nM PDBu did not down-regulate PKC activity in KM12L4a cells, activation of PKC appeared to be responsible for the observed protection conferred by PDBu. PDBu-induced alterations in drug accumulation may account for its protective effects against these cytotoxic drugs, because both PDBu and the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate significantly reduced accumulation of [3H] VCR and [14C]ADR in the cultured human colon cancer cells. Unsaturated diacylglycerols are structural and functional analogues of phorbol ester PKC activators that are present in the lumen of the colon. We found that treatment of KM12L4a human colon cancer cells with the diacylglycerol 1-oleoyl-2-acetyl-sn-glycerol (OAG) significantly reduced [14C]ADR and [3H]VCR accumulation in the cells. The effects of OAG were dose dependent at physiological diacylglycerol concentrations and were completely reversed by the protein kinase inhibitor H7. OAG, which is rapidly metabolized in cultured cells, did not protect KM12L4a cells against the cytotoxic drugs in our 96-hr in vitro chemosensitivity assay. However, rapid metabolism of diacylglycerols should not limit their capacity to activate PKC in the colonic epithelium in vivo, because that tissue is chronically exposed to replenished supplies of unsaturated diacylglycerols in the intestinal tract. Our results provide evidence that unsaturated diacylglycerols may be environmental factors that contribute to the intrinsic drug resistance of colon cancer in vivo by reducing drug accumulation in the cancer cells.
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PMID:In vitro model for intrinsic drug resistance: effects of protein kinase C activators on the chemosensitivity of cultured human colon cancer cells. 201 56

Kinetic properties of phosphofructokinase 2 (PFK2) and regulation of glycolysis by phorbol 12-myristate 13-acetate (PMA) and insulin were investigated in highly glycolytic HT29 colon cancer cells. PFK2 was found to be inhibited by citrate and, to a lesser extent, by phosphoenolpyruvate and ADP, but to be insensitive to inhibition by sn-glycerol phosphate. From these kinetic data, PFK2 from HT29 cells appears different from the liver form, but resembles somewhat the heart isoenzyme. Fructose 2,6-bisphosphate (Fru-2,6-P2) levels, glucose consumption and lactate production are increased in a dose-dependent manner in HT29 cells treated with PMA or insulin. The increase in Fru-2,6-P2 can be related to an increase in the Vmax. of PFK2, persisting after the enzyme has been precipitated with poly(ethylene glycol), without change in the Km for fructose 6-phosphate. The most striking effects of PMA and insulin on Fru-2,6-P2 production are observed after long-term treatment (24 h) and are abolished by actinomycin, cycloheximide and puromycin, suggesting that protein synthesis is involved. Furthermore, the effects of insulin and PMA on glucose consumption, lactate production, Fru-2,6-P2 levels and PFK2 activity are additive, and the effect of insulin on Fru-2,6-P2 production is not altered by pre-treatment of the cells with the phorbol ester. This suggests that these effects are exerted by separate mechanisms.
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PMID:Phosphofructokinase 2 and glycolysis in HT29 human colon adenocarcinoma cell line. Regulation by insulin and phorbol esters. 216 13

Alkylglycerols are naturally occurring bioactive ether lipids found in great abundance in the livers of many marine species. In this study, we evaluated the differentiation-promoting potential of a methoxy substituted alkylglycerol--1-O (2 methoxy) hexadecyl glycerol (MHG)--to promote a more benign or differentiated phenotype in human colon cancer cells. Three cell lines with different biological and phenotypic properties were used. They were the moderately differentiated and growth factor-responsive Moser, the growth factor-unresponsive and malignant HT29, and the poorly differentiated and growth factor-unresponsive HCT116. Treatment of these cell lines with MHG resulted in a downmodulation of cellular proliferation, a reduced propensity for anchorage-independent growth, and a reduced capacity in cellular invasion. Induction of the colon-associated and differentiation-related molecule carcinoembryonic antigen was also observed in the three cell lines. Induction of the transformation-sensitive and differentiation-related glycoprotein fibronectin was observed in the HT29 cells. It is concluded that MHG was biologically active and promoted a more benign or differentiated phenotype in these colon cancer cells. Since differentiation-inducing agents may possess chemoprevention properties, the use of MHG and the alkylglycerols in inducing differentiation or in chemoprevention of malignant diseases warrants further investigation.
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PMID:Differentiation-promoting effect of 1-O (2 methoxy) hexadecyl glycerol in human colon cancer cells. 1004 81

In comparison with other OECD countries with good cancer registries, New Zealand has the highest mortality rate of colon cancer, second highest of breast cancer and third highest of prostate cancer. A possible association with heterocyclic amine consumption has been suggested for each of these cancers. Studies of locally cooked meat suggest that the main contributors to heterocyclic amines in the New Zealand diet would be well-cooked beef, chicken and pork. Well-cooked beef steak, and the specific heterocyclic amine, IFP, showed a weak positive correlation with prostate cancer risk in the New Zealand population, but no studies thus far have considered the role of meat cooking practices or heterocyclic amines in the development of other cancers. The Maori and Pacific Island people, despite a superficially similar diet, have a substantially lower incidence of colon cancer than people of Caucasian origin. These differences are particularly intriguing in view of a report that a very high percentage of these people have a fast acetylator phenotype-a factor suggested to augment the effect of well-cooked red meat in other populations. The three population groups are known to differ in their preferences for meat type (including processed meats), and there are anecdotal suggestions that they may differ in preferred cooking methods. More detailed population studies are warranted to establish the role of meat, meat processing, cooking methods and the interaction with food plants and/or with genotype and phenotype in New Zealand.
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PMID:Meat consumption, cancer risk and population groups within New Zealand. 1235 Nov 61

Alkaline sphingomyelinase (alk-SMase) is a new member of the NPP (nucleotide pyrophosphatase/phosphodiesterase) family that hydrolyses SM (sphingomyelin) to generate ceramide in the intestinal tract. The enzyme may protect the intestinal mucosa from inflammation and tumorigenesis. PAF (platelet-activating factor) is a pro-inflammatory phospholipid involved in pathogenesis of inflammatory bowel diseases. We examined whether alk-SMase can hydrolyse and inactivate PAF. [3H]Octadecyl-labelled PAF was incubated with purified rat intestinal alk-SMase or recombinant human alk-SMase expressed in COS-7 cells. The hydrolytic products were assayed with TLC and MS. We found that alkSMase cleaved the phosphocholine head group from PAF and generated 1-O-alkyl-2-acetyl-sn-glycerol. Differing from the activity against SM, the activity against PAF was optimal at pH 7.5, inhibited by EDTA and stimulated by 0.1-0.25 mM Zn2+. The activity was abolished by site mutation of the predicted metal-binding sites that are conserved in all NPP members. Similar to the activity against SM, the activity against PAF was dependent on bile salt, particularly taurocholate and taurochenodeoxycholate. The V(max) for PAF hydrolysis was 374 mumol x h(-1) x (mg of protein)(-1). The hydrolysis of PAF and SM could be inhibited by the presence of SM and PAF respectively, the inhibition of PAF hydrolysis by SM being stronger. The PAF-induced MAPK (mitogen-activated protein kinase) activation and IL-8 (interleukin 8) release in HT-29 cells, and chemotaxis in leucocytes were abolished by alk-SMase treatment. In conclusion, alk-SMase hydrolyses and inactivates PAF by a phospholipase C activity. The finding reveals a novel function, by which alk-SMase may counteract the development of intestinal inflammation and colon cancer.
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PMID:Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity. 1625 17

It has recently been suggested that an Na(+)-dependent carrier-mediated transport system is involved in intestinal glycerol absorption. Such a transport system is of general interest as a possible pathway of drug delivery and a target of drug development. However, the Na(+)-dependent mechanism of cellular glycerol uptake has not been fully clarified in the small intestine or in any other organ. The purpose of the present study was to examine glycerol uptake in the HCT-15 human colon cancer cell line, which was found to be able to perform Na(+)-dependent glycerol uptake, to determine the transport characteristics and help identify such glycerol transport systems. The uptake of glycerol in HCT-15 cells was highly saturable with a Michaelis constant of 15.0 microM and a maximum uptake rate of 11.9 pmol/min/mg protein, accompanied by minimal unsaturable transport; it was reduced markedly under Na(+)-free conditions, indicating Na+ requirement. Glycerol uptake was also reduced by 2,4-dinitrophenol, a metabolic inhibitor. These results suggest that a carrier-mediated glycerol transport system, which is Na(+)-dependent and secondarily active, is present in HCT-15 cells. The transport system could be specific for glycerol and some analogous compounds with hydroxyl groups, since glycerol uptake was inhibited by some alcohols and compounds related to glycerol, such as 1,2-propanediol and glycerol 3-phosphpate. However, it may represent a high affinity transport system, which is different from the one in the small intestine, because the Michaelis constant of 15.0 microM is about 50-fold lower than that observed in the rat small intestine. In conclusion, this is the first study to demonstrate an Na(+)-dependent carrier-mediated glycerol transport in an established cell line. This will help in identifying a group of Na(+)-dependent glycerol transport systems and elucidating their transport mechanisms, although the one found in HCT-15 cells in this study seems to be different from one previously found in the rat small intestine.
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PMID:Glycerol uptake in HCT-15 human colon cancer cell line by Na(+)-dependent carrier-mediated transport. 1639 29

Hot dogs contain apparent N-nitroso compounds (ANC) and ANC precursors (ANCP). ANCP purification was followed by nitrosation, sulfamic acid treatment, and analysis for ANC. Aqueous hot dog extracts were adsorbed on silica gel, which was eluted with MeCN and MeOH. The MeOH eluate was adsorbed on cation exchange resin (H+ form) and eluted with NH4OH. Eluted ANCP traveled at moderate speeds in high-performance liquid chromatography (HPLC) on amino and Pb2+ columns. Gas chromatography-mass spectrometry (GC-MS) of trimethylsilyl (TMS) derivatives of crude water extract indicated the presence of glycerol, phosphate, lactic acid, and two monosaccharides. GC-MS of TMS derivatives of Pb2+ column HPLC eluates indicated that ANCP included 1-deoxy-N-1-glucosyl glycine. The nitrosated NH4OH eluate showed 4x background mutagenic activity for Salmonella typhimurium TA-100. Un-nitrosated fractions showed 2x background activity. Although tryptophan nitrosation gave 88% ANC yield, tryptophan is probably not a major ANCP in hot dogs. Hot dog patties prepared with or without sucrose or glucose showed similar ANC and ANCP levels. We discuss possible implications of these findings for the etiology of colon cancer.
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PMID:Partial purification from hot dogs of N-nitroso compound precursors and their mutagenicity after nitrosation. 1684 63

The HCT-15 human colon cancer cell line has a Na(+)-dependent carrier-mediated transport system for the uptake of glycerol. A similar transport system has been suggested to be present also in the small intestine and is of interest with regard to its role in the absorption of glycerol and possibly some structurally related compounds. To help clarifying functional characteristics of such glycerol transport systems, we examined the effect of butyrate, an agent known to facilitate the differentiation of cells, on glycerol uptake in HCT-15 cells. The uptake of glycerol (0.4 microM) was found to be about 5-fold greater in HCT-15 cells pretreated with butyrate (2 mM) for 24 h than in those untreated. The increase in the uptake by the butyrate treatment was due to an increase in the maximum transport rate. The effect of butyrate was almost completely suppressed when actinomycin D, an inhibitor of gene transcription, and cycloheximide, an inhibitor of protein synthesis, were added to the medium during the butyrate treatment. These results support the suggestion that a specific carrier protein is involved in glycerol uptake by HCT-15 cells and the carrier protein is one of those inducible by butyrate-induced cell differentiation.
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PMID:Enhanced uptake of glycerol by butyrate treatment in HCT-15 human colon cancer cell line. 1760 20

Anti-tumor-associated glycoprotein (TAG)-72 PEG-immunoliposomes (PILs) were prepared by conjugation of Fab' fragments of recombinant humanized monoclonal antibody, HuCC49, to sterically stabilize unilamellar liposomes (90-110 nm in diameter) to target TAG-72-overexpressing cancer cells. The liposomes consisted of 1-palmitonyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC), 92 mol percent, O,O'-dymyrisyl-N-lysyl aspartate (DMKD cationic lipid), 4 mol percent, distearoyl-phosphatidyl-ethanolamine-polyethylene glycol 2000 (DSPE-PEG(2000)), 3 mol percent and DSPE-maleimide (DSPE-PEG(2000)-Mal), 1 mol percent. These anti-TAG-72 PILs were able to adhere to the surface of TAG-72-overexpressing LS174 T human colon cancer cells more effectively than conventional liposomes. Also, in vitro gene transfection of the LS174 T cells by the anti-TAG-72 PILs in the presence of a high concentration of fetal bovine serum (up to 60%) was greater than that by conventional cationic lipoplexes. Intravenously administered anti-TAG-72 PILs efficiently localized in the LS174 T tumor tissues, while the non-targeted conventional liposomes did not. Intravenous administration of the anti-TAG-72 PILs containing plasmids encoding antiangiogenic proteins, such as angiostatin K1/3, endostatin and saxatilin, significantly inhibited in vivo growth of LS174 T tumors and angiogenesis in the tumor tissues. These results demonstrated the potential of TAG-72-mediated targeting of immunoliposomes as a modality for systemic gene delivery to human colon cancer cells.
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PMID:Targeted gene therapy of LS174 T human colon carcinoma by anti-TAG-72 immunoliposomes. 1830 54

Lysophosphatidic acid (LPA; 1- or 2-acyl-sn-glycerol-3-phosphate) is a phospholipid that is involved in numerous normal physiological and pathological processes such as brain development, blood vessel formation, embryo implantation, hair growth, neuropathic pain, lung fibrosis and colon cancer. Most of these functions are mediated by G protein-coupled receptors (GPCRs) specific to LPA. So far, six GPCRs for LPA have been identified: LPA(1)/Edg2, LPA(2)/Edg4, LPA(3)/Edg7, LPA(4)/GPR23/P2Y9, LPA(5)/GPR92 and LPA(6)/P2Y5. An intracellular target of LPA has also been proposed. Among the LPA receptors, LPA(3) is unique in that it is activated significantly by a specific form of LPA (2-acyl LPA with unsaturated fatty acids) and is expressed in a limited number of tissues such as the reproductive organs. Recent studies have shown that LPA(3)-mediated LPA signaling is essential for proper embryo implantation and have revealed an unexpected genetic linkage between LPA and prostaglandin signaling. Here we review recent advances in the study of LPA(3), especially studies using LPA(3)-deficient mice. In addition, we focus on the agonists and antagonists that are specific to each LPA receptor as important tools for the functional study of LPA signaling.
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PMID:LPA(3), a unique G protein-coupled receptor for lysophosphatidic acid. 2023 Aug 55


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