Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of proteases can play an important role in apoptotic cell death induced by anticancer drugs. To assess involvement of activation of cysteine and serine proteases in anticancer drug-induced apoptosis, we tested effect of inhibitors of cysteine and serine proteases on sensitivity to anticancer drugs in MKN45 gastric cancer cells. Cytotoxic effect by adriamycin (ADM), SN-38 (active form of irrinotecan) and cisplatin (CDDP) was significantly prevented by cotreatment with Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk) (p<0.01), a pancaspase inhibitor compared with drug alone using MTT assay. In contrast, cotreatment with N-acetyl-Tyr-Val-Ala-Asp aldehyde (AC-YVAD-CHO), a caspase 1 inhibitor did not prevent any cytotoxic effect of these drugs. Cotreatment of N-acetyl-Asp-Glu-Val-Asp aldehyde (AC-DEVD-CHO), a caspase 3 inhibitor prevented cytotoxic effect of VP-16 and SN-38 (p<0.01). Prevention of these cytotoxic effects by caspase inhibitors was not dose-dependent. Cotreatment of N-tosyl-L-lysyl chloromethylketone (TLCK), a serine protease inhibitor significantly prevented cytotoxic effect of ADM, SN-38, 5-fluorouracil (5-FU) and CDDP in a slight dose-dependent manner (p<0.01) except for etoposide (VP-16) and docetaxel (TXT), while an other serine protease inhibitor, N-tosyl-L-phenylalanyl chloromethylketone (TPCK) did not prevent any anticancer drug-induced cytotoxic effect. These effects were associated with prevention of internucleosomal DNA ladder formation in apoptosis. Further, protease inhibitors did not block induction of cytochrome c, that can explain the partial effect of prevention by anticancer-induced cell death. These results suggest that anticancer drug-induced cytotoxic effect is mediated by activation of serine protease (caspase-independent) as well as caspase-dependent pathway leading to apoptotic cell death, and that protease-independent pathway may also be involved in apoptotic pathways. The involvement of protease in signal transduction pathways may differ in cytotoxic action of drugs in gastric cancer cells.
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PMID:Effect of inhibitors of cysteine and serine proteases in anticancer drug-induced apoptosis in gastric cancer cells. 1135 Dec 55

Gastric cancer is the second most frequent cause of death from cancer in the world and the leading cause of death from cancer in China. In September 1995, we launched a randomized multi-intervention trial to inhibit the progression of precancerous gastric lesions in Linqu County, Shandong Province, an area of China with one of the world's highest rates of gastric cancer. Treatment compliance was measured by pill counts and quarterly serum concentrations of vitamin C, vitamin E and S-allyl cysteine. In 1999, toxicity information was collected from each trial participant to evaluate treatment-related side-effects during the trial. Compliance rates were 93% and 92.9% for 39 months of treatment with the vitamins/mineral and garlic preparation, respectively. The means for serum concentrations of vitamins C and E were 7.2 microg/ml and 1695 microg/dl among subjects in the active treatment groups compared with 3.1 microg/ml and 752 microg/dl among subjects in the placebo treatment group, respectively. No significant differences in side-effects were observed between the placebo treatment group and the vitamins/mineral and garlic preparation treatment groups during the 39-month trial period.
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PMID:An intervention trial to inhibit the progression of precancerous gastric lesions: compliance, serum micronutrients and S-allyl cysteine levels, and toxicity. 1143 13

AIM:To investigate the interference of methionine-free parenteral nutrition plus 5-Fu (-MetTPN+5-Fu) in gastric cancer cell kinetics and the side effects of the regimen.METHODS:Fifteen patients with advanced gastric cancer were randomly divided intotwo groups, 7 patients were given preoperatively a seven-day course of standard parenteral nutrition in combination with a five-day course of chemotherapy (sTPN+5-Fu), while the other 8 patients were given methionine-deprived parenteral nutrition and 5-Fu (-MetTPN+5-Fu). Cell cycles of gastric cancer and normal mucosa were studied by flow cytometry (FCM). Blood samples were taken to measure the serum protein, methionine (Met) and cysteine (Cys) levels, and liver and kidney functions.RESULTS:As compared with the results obtained before the treatment, the percentage of G(0)/G(1) tumor cells increased and that of S phase decreased in the -MetTPN+5-Fu group, while the contrary was observed in the sTPN+5-Fu group. Except that the ALT, AST and AKP levels were slightly increased in a few cases receiving -MetTPN+5-Fu, all the other biochemical parameters were within normal limits. Serum Cys level decreased slightly after the treatment in both groups. Serum Met level of patients receiving sTPN+5-Fu was somewhat higher after treatment than that before treatment; however, no significant change occurred in the -MetTPN+5-Fu group, nor operative complications in both groups.CONCLUSION:-MetTPN+5-Fu exerted a suppressive effect on cancer cell proliferation, probably through a double mechanism of creating a state of "Met starvation" adverse to the tumor cell cycle, and by allowing 5-Fu to kill specifically cells in S phase. Preoperative shortterm administration of -MetTPN+5-Fu had little undesirable effect on host metabolism.
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PMID:A study of preoperative methionine-depleting parenteral nutrition plus chemotherapy in gastric cancer patients. 1181 69

MYC, ERBB2, MET, FGFR2, CCNE1, MYCN, WNT2, CD44, MDM2, NCOA3, IQGAP1 and STK6 loci are amplified in human gastric cancer. It has been reported that the gene corresponding to EST H16094 is co-amplified with ERBB2 gene in human gastric cancer. Here, we identified and characterized the gene corresponding to EST H16094 by using bioinformatics. BLAST programs revealed that EST H16094 was derived from the uncharacterized MGC9753 gene. Two ORFs were predicted within human MGC9753 mRNA, and ORF1 (nucleotide position 18-980 of NM_033419.1) was predicted as the coding region of human MGC9753 mRNA based on comparative genomics. Nucleotide sequence of mouse Mgc9753 mRNA was next determined in silico by modification of AK052486 cDNA (deleting C at the nucleotide position 37). Human MGC9753 and mouse Mgc9753 proteins were 320-amino-acid seven-transmembrane receptors with the N-terminal six-cysteine domain and an N-glycosylation site (85.0% total-amino-acid identity). Human MGC9753 protein showed 90.6% total-amino-acid identity with human CAB2 aberrant protein, which lacked the third-transmembrane domain of MGC9753 due to frame shifts within ORF. Human MGC9753 gene, consisting of eight exons, were clustered with PPP1R1B, STARD3, TCAP, PNMT, ERBB2, MGC14832 and GRB7 genes within the 120-kb region. PPP1R1B, STARD3, MGC9753, ERBB2 and GRB7 genes are co-amplified in several cases of gastric cancer. This is the first report on comprehensive characterization of the amplicon around the PPP1R1B-STARD3-TCAP-PNMT-MGC9753-ERBB2-MGC14832-GRB7 locus on human chromosome 17q12.
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PMID:MGC9753 gene, located within PPP1R1B-STARD3-ERBB2-GRB7 amplicon on human chromosome 17q12, encodes the seven-transmembrane receptor with extracellular six-cystein domain. 1273 7

Microarray analyses is applied for prognosis of gastric cancer, including risk assessments of lymph-node metastasis and peritoneal dissemination. EST AA769445 derived from an unknown gene is reported to be frequently down-regulated in intestinal-type gastric cancer based on microarray analyses. Here, we identified and characterized the gene corresponding to EST AA769445 by using bioinformatics. EST AA769445 overlapped with MGC29506 cDNA (BC021275) and PACAP cDNA (AF338109). MGC29506 protein (189 aa) and PACAP protein (123 aa) were identical in codon 1-59, but were divergent in the C-terminal region due to a frame shift caused by sixteen-base insertion in PACAP cDNA. MGC29506 and PACAP were derived from the same gene, consisting of four exons, due to alternative splicing of alternative splice-acceptor-site type. Fourteen human ESTs were the MGC29506 type, while one human EST was the PACAP type. MGC29506 was the major isoform of the MGC29506/PACAP gene on human chromosome 5q31.2. MGC29506 orthologs in other species were next searched for. AK088094 and AK008016 cDNAs with nucleotide substitutions resulting in four-amino-acid substitutions were derived from mouse Mgc29506 gene. Rat Mgc29506 gene was identified in the rat genome draft sequence AC135285. ESTs AJ396310 and AJ441435 were derived from chicken Mgc29506 gene, while ESTs BW315632 and BW251767 from ciona mgc29506 gene. N-terminal signal peptide, six cysteine residues and other amino acids were conserved among human, mouse, rat, chicken, and ciona MGC29506 proteins. MGC29506 gene, frequently down-regulated in intestinal-type gastric cancer, was found to encode secreted-type protein with six conserved cysteine residues.
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PMID:MGC29506 gene, frequently down-regulated in intestinal-type gastric cancer, encodes secreted-type protein with conserved cysteine residues. 1279 99

Survivin plays an important role in cancer development. We aim to show here that suppression of survivin expression or function by antisense and dominant-negative (DN) mutant can inhibit gastric cancer carcinogenesis and angiogenesis in vivo. Plasmid constructs expressing survivin antisense and DN mutant replacing the cysteine residue at amino acid 84 with alanine (Cys84Ala) were prepared and introduced into BCG-823 and MKN-45 gastric cancer cells to establish stable transfectants. We showed that both antisense and DN mutant stable transfectants exhibited abnormal morphology, with decreased cell growth and increased rate of spontaneous apoptosis and mitotic catastrophe. Furthermore, in nude mice xenografts, these cells exhibited decreased de novo gastric tumor formation and reduced development of angiogenesis. Results from these studies strongly suggest that survivin is a promising target for gastric cancer treatment.
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PMID:Suppression of survivin expression inhibits in vivo tumorigenicity and angiogenesis in gastric cancer. 1463 97

The human monoclonal antibody PAM-1 was isolated from a patient with stomach cancer. The germ-line coded IgM antibody identifies a recently described 130 kDa variant of CFR-1 (cysteine-rich fibroblast growth factor receptor 1). This CFR-1/PAM-1 receptor is post-transcriptionally modified and over-expressed on human epithelial tumors and carcinoma pre-cancer lesions such as H. pylori induced gastritis, intestinal metaplasia and dysplasia of the stomach, ulcerative colitis-related dysplasia and adenomas of the colon, Barrett metaplasia and dysplasia of the esophagus, squamous cell metaplasia and dysplasia of the lung and cervical intraepithelial neoplasia. Furthermore, the expression of CFR-1/PAM-1 correlates with the proliferation rate and increases with the grade of malignancy. This study demonstrates that the human monoclonal antibody PAM-1 inhibits cell growth and induces apoptosis, in vitro and in vivo. Both, the unique tumor-specific expression of the CFR-1/PAM-1 receptor and the growth inhibitory effect of the PAM-1 antibody makes this combination a good diagnostic and therapeutic tool for all kinds of epithelial cancers and precursor lesions.
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PMID:CFR-1 receptor as target for tumor-specific apoptosis induced by the natural human monoclonal antibody PAM-1. 1501 Aug 72

We have investigated the effects of three types of procyanidin isolated from apple (Rosaceae Malus pumila) on DNA of human stomach cancer KATO III cells. Induction of apoptosis by these procyanidins was observed in human stomach cancer KATO III cells. Morphological changes showing apoptotic bodies were observed in the KATO III cells treated with procyanidins. The fragmentation of DNA by procyanidins to oligonucleosomal-sized fragments, a characteristic of apoptosis, was observed to be concentration- and time-dependent in the KATO III cells. N-acetyl-L-cysteine, an antioxidant, suppressed the DNA fragmentation induced by these procyanidins. The present study shows that the suppression of KATO III cell-growth by three types of procyanidin results from the induction of apoptosis by these compounds, and that active oxygen is involved in the induction of apoptosis by these compounds in the KATO III cells.
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PMID:Induction of apoptosis by three types of procyanidin isolated from apple (Rosaceae Malus pumila) in human stomach cancer KATO III cells. 1513 14

Recent studies have suggested that the expression of interleukin-8 (IL-8) directly correlates with the vascularity of human gastric carcinomas. In this study, the effect of IL-1beta on IL-8 expression in human gastric cancer TMK-1 cells and the underlying signal transduction pathways were investigated. IL-1beta induced the IL-8 expression in a time- and concentration-dependent manner. IL-1beta induced the activation of extracellular signal-regulated kinases-1/2 and P38 mitogen-activated protein kinase (MAPK), but not the activation of c-jun amino-terminal kinse and Akt. Specific inhibitors of MEK-1 (PD980590) and P38 MAPK (SB203580) were found to suppress the IL-8 expression and the IL-8 promoter activity. Expression of vectors encoding a mutated-type MEK-1 and P38 MAPK resulted in decrease in the IL-8 promoter activity. IL-1beta also induced the production of reactive oxygen species (ROS). N-acetyl cysteine (NAC) prevented the IL-1beta-induced ROS production and IL-8 expression. In addition, exogenous H2O2 could induce the IL-8 expression. Deletional and site-directed mutagenesis studies on the IL-8 promoter revealed that activator protein-1 (AP-1) and nuclear factor (NF)-kappaB sites were required for the IL-1beta-induced IL-8 transcription. Electrophoretic mobility shift assay confirmed that IL-1beta increased the DNA-binding activity of AP-1 and NF-kappaB. Inhibitor (PD980590, SB203580) and ROS scavenger (NAC) studies revealed that the upstream signalings for the transcription factors AP-1 and NF-kappaB were MAPK and ROS, respectively. Conditioned media from the TMK-1 cells pretreated with IL-1beta could remarkably stimulate the in vitro growth of HUVEC and this effect was partially abrogated by IL-8-neutralizing antibodies. The above results suggest that MAPK-AP-1 and ROS-NF-kappaB signaling pathways are involved in the IL-1beta-induced IL-8 expression and that these paracrine signaling pathways induce endothelial cell proliferation.
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PMID:Interleukin-1beta stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells. 1520 68

Bone morphogenetic proteins (BMPs) are implicated in the regulation of morphogenesis and proliferation during embryogenesis and carcinogenesis. We have previously reported over-expression of BMP4 in diffuse-type gastric cancer cells. BMP signaling is regulated by tissue-specific expression of ligands and receptors as well as by secreted-type antagonists, such as CKTSF1B1 (Gremlin), CER1 (Cerberus 1), Noggin, SOSTDC1 (Ectodin), and Chordin. Here, we identified two novel genes related to CKTSF1B1 and CER1 by using bioinformatics. Two novel members of human CKTSF1B gene family were designated CKTSF1B2 (GREM2 or PRDC) and CKTSF1B3 (GREM3 or DANTE). FLJ21195 (BC046632.1) was the representative human CKTSF1B2 cDNA, and CKTSF1B2 gene was mapped to human chromosome 1q43. Human CKTSF1B2 showed 94.0% total amino-acid identity with mouse Cktsf1b2 (Prdc). FLJ38607 (AK095926.1) was the representative human CKTSF1B3 cDNA, and CKTSF1B3 gene was mapped to human chromosome 19p13.2. Human CKTSF1B3 showed 61.9% total amino-acid identity with mouse Cktsf1b2 (Dante). N-terminal signal peptide and DAN domain with nine cysteine residues were conserved among CKTSF1B1, CKTSF1B2, CKTSF1B3 and CER1. Phylogenetic analyses revealed that CKTSF1B2 was more related to CKTSF1B1, and that CKTSF1B3 was more related to CER1. CKTSF1B1, CKTSF1B2, CKTSF1B3 and CER1 constitute the CKTSF1B family among secreted-type cysteine knot superfamily proteins. This is the first report on identification and characterization of the human CKTSF1B2 and CKTSF1B3 genes.
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PMID:Identification and characterization of human CKTSF1B2 and CKTSF1B3 genes in silico. 1525 11


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