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)

Tumor promoting phorbol esters, 12-O-tetradecanoylphorbol-13-acetate (TPA) and phorbol-12,13-dibutyrate (PDBu), significantly enhanced the growth of human gastric cancer cell line TMK-1, whilst activating protein kinase C. The time course of 125I-epidermal growth factor (EGF) binding to TMK-1 cells after TPA treatment showed a decrease in the number of EGF receptors on TMK-1 cells within 3 hr. Autophosphorylation of EGF receptor decreased in accordance with the decrease of EGF binding by TPA treatment. Scatchard plot analysis of TMK-1 cells after TPA treatment showed that high affinity EGF receptor disappeared at 3hr but the number of EGF receptors increased at 24 hr. These findings suggest that tumor promoting phorbol esters stimulate the cell growth through activation of protein kinase C and modification of EGF receptor of human gastric cancer cell line TMK-1.
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PMID:The effect of phorbol esters on cell growth and epidermal growth factor receptor modulation in a human gastric carcinoma cell line TMK-1. 263 48

The isoform of protein kinase C responsible for the inhibition of histamine-stimulated adenylate cyclase by the phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), has been investigated in a particulate fraction prepared from the human gastric cancer cell line HGT-1. The alpha and epsilon isoforms of protein kinase C were detected in HGT-1 cells and in a 40,000 x g particulate fraction by immunoblotting procedures. The inhibitory effect of TPA on histamine-stimulated adenylate cyclase was enhanced by the presence of Ca2+, but decreased in a concentration-dependent manner by anti-peptide antibody to protein kinase C alpha, but not to protein kinase C epsilon. Addition of Ca2+ and TPA to the 40,000 x g particulate fraction stimulated the phosphorylation of the protein kinase C substrate myelin basic peptide 4-14. Protein kinase C alpha is probably the isoform responsible for inhibition of histamine-stimulated adenylate cyclase in HGT-1 cells.
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PMID:The alpha isoform of protein kinase C inhibits histamine-stimulated adenylate cyclase activity in a particulate fraction of the human gastric cancer cell line HGT-1. 754 78

The human platelet-activating factor receptor (PAFR) gene is transcribed by two distinct promoters (promoter 1 and promoter 2) to generate two transcripts (designated as PAFR transcript 1 and PAFR transcript 2), though their open reading frames are identical. By primer extension analysis to discriminate two transcripts, we found that the levels of PAFR transcript 1 (leukocyte-type), but not PAFR transcript 2 (tissue-type), are upregulated by PAF as well as by 12-O-tetradecanoylphorbol-13-acetate (TPA) in the human stomach cancer cell line (JR-St cells) which expresses both functional PAFR transcript 1 and PAFR transcript 2 endogenously. Functional analysis of the promoter 1 with a transient expression assay using chloramphenicol acetyltransferase (CAT) gene as a reporter showed that both PAF and TPA activated the promoter 1 but not the deleted promoter lacking the three consensus binding sites for NF-kappa B located from -571 bp to -459 bp. These findings suggest a molecular mechanism of positive regulation of PAFR gene expression by PAF through NF-kappa B, possibly by a phosphorylation reaction involving protein kinase C by PAF.
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PMID:Platelet-activating factor (PAF) positively auto-regulates the expression of human PAF receptor transcript 1 (leukocyte-type) through NF-kappa B. 780 42

BE-23372M, a novel protein tyrosine kinase inhibitor, was isolated from the culture broth of a fungus. The producing strain, F23372, was identified as Rhizoctonia solani, based on the cultural and morphological characteristics. The active principle was extracted from the mycelium with acetone and purified by solvent extraction, silica gel column chromatography and Sephadex LH-20 column chromatography. BE-23372M showed strong inhibitory activity against EGF receptor kinase with IC50 values of 0.02 and 0.03 microM on two different substrates, whereas IC50 values against protein kinase C and cAMP-dependent protein kinase were 4.5 and > 20 microM, respectively. The compound inhibited the growth of A431 human epidermoid carcinoma and MKN-7 human stomach cancer cell lines with IC50 values of 8 and 24 microM, respectively.
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PMID:BE-23372M, a novel protein tyrosine kinase inhibitor. I. Producing organism, fermentation, isolation and biological activities. 817 80

The HGT-1 gastric cancer cell line was used to determine the actions of protein kinase C on the stimulation of adenylate cyclase by the human histamine H2 receptor, and the receptors for gastric inhibitory polypeptide and truncated glucagon like peptide 1 (TGLP-1). Suspensions of HGT-1 cells were preincubated with the activator of protein kinase C, 12-O-tetradecanoylphorbol 13-acetate (TPA, 100 nmol/l), for 10 minutes. The subsequent cyclic adenosine monophosphate (AMP) response to 0.5 mmol/l histamine or 100 nmol/l TGLP-1 was reduced by comparison with control cells preincubated in the absence of TPA. The cyclic AMP response to 100 nmol/l gastric inhibitory polypeptide was enhanced by preincubation with TPA, while the responses to cholera toxin and forskolin were unaffected. Preincubation with pertussis toxin prevented the enhancement of the gastric inhibitory polypeptide response by TPA, suggesting an involvement of an inhibitory guanine nucleotide regulatory subunit of the Gi class, but did not change the inhibition of histamine stimulation. In conclusion, activation of protein kinase C produces a specific inhibition of the effects of histamine and TGLP-1 on adenylate cyclase activity in a human gastric cancer cell line by acting at a site close to their receptors.
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PMID:Protein kinase C inhibits cyclic adenosine monophosphate generation by histamine and truncated glucagon like peptide 1 in the human gastric cancer cell line HGT-1. 839 30

In the human gastric adenocarcinoma cell line AGS the effects of the protein-kinase-C-activating phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), the protein kinase C inhibitor staurosporine, the adenylate-cyclase activating agent forskolin, and the permeable dibutyryl-adenosine 3',5'-monophosphate (Bt2cAMP) on the proliferation were assessed. Cell counting followed 5 days of incubation. Prolonged activation of protein kinase C by TPA, inhibition of protein kinase C by staurosporine, activation of adenylate cyclase by forskolin or a direct increase of the intracellular cAMP level all result in a dose-dependent growth inhibition of AGS gastric tumour cells. Half-maximal inhibition was achieved at 100 pM for TPA, 1 nM for staurosporine, 20 microM for forskolin, and 600 microM for Bt2cAMP. It is concluded that protein kinase C and adenylate cyclase play a fundamental role in the growth of AGS gastric cancer cells. Interference with these enzymes involved in the signal transduction of growth regulation in tumour cells may represent a target in the development of new antiproliferative principles.
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PMID:Protein kinase C and adenylate cyclase as targets for growth inhibition of human gastric cancer cells. 840 80

CGP 41251 (4'-N-benzoyl staurosporine, CAS 120685-11-2) has been shown to exert increased selectivity for the inhibition of protein kinase C (PKC) activity. In the present study the effect of CGP 41251 formulated in gelucire as an antitumor agent was studied in various types of murine and human tumor models. When administered at a dose of 75 mg/kg 3 times daily for 9 days, CGP 41251 prolonged the life span of the mice bearing B16 melanoma (ILS = 36%). CGP 41251, administered orally at doses of 25-225 mg/kg once daily for 9 days, however, did not show distinct efficacy in four kinds of murine tumor models (B16 melanoma, colon 26, colon 38 and M5076). In s.c.inoculated human tumor xenograft models, CGP 41251, administered orally at a dose of 200 mg/kg once daily for 4 weeks showed a broad antitumor spectrum. CGP 41251 inhibited the growth of gastric cancer (H-55), colorectal cancer (H-26), breast cancer (H-31) and lung cancer (H-74 and LC-376) with inhibition rates of 58-80%. In a histopathologic study, increase in central necrosis and condensed nuclei and vacuolar degeneration were observed, but there was no structural destruction by the treatment of CGP 41251. In addition, CGP 41251 decreased the number of PCNA (proliferating cell nuclear antigen) immunoreactive cells in human tumor cells H-55, H-26 and H-74. These results indicate that CGP 41251 shows a broad antitumor spectrum against human tumors, and it is suggested that CGP 41251 is a promising oral antitumor agent which has a novel mechanism of action.
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PMID:Antitumor activity of the new selective protein kinase C inhibitor 4'-N-benzoyl staurosporine on murine and human tumor models. 892 45

The histidine decarboxylase (HDC) gene is regulated transcriptionally by gastrin and phorbol 12-myristate 13-acetate (PMA) through a protein kinase C (PKC)-related pathway. To determine the role of AP-1 (fos/jun) in the regulation of the HDC promoter, gastric cancer (AGS-B) cells stably expressing the cholecystokinin-B/ gastrin receptor and the 1.8-kb human (h) HDC-luciferase (luc) construct were cotransfected with constructs expressing c-fos and c-jun. Overexpression of c-fos and c-jun activated the HDC promoter in a dose-dependent fashion in 1.8-kb hHDC-luc/AGS-B cells as well as in transfected F9 embryonal carcinoma cells, which lack endogenous AP-1 activity. PMA was unable to activate the HDC promoter in F9 cells, which were not transfected with c-fos and c-jun. Gastrin stimulation increased c-fos and c-jun mRNA abundance and AP-1-dependent transcriptional activity, as assessed by a reporter construct in which the CAT reporter gene is under the control of a 12-O-tetradecanoylphorbol-13-acetate response element multimer. Gastrin-stimulated HDC promoter activity was blocked by transfection of c-fos antisense and dominant negative c-jun expression constructs. Finally, overexpression of c-fos and c-jun activated the hHDC promoter through a downstream cis-acting element (gastrin response element), which does not bind AP-1. In conclusion, activation of AP-1 is essential for gastrin-stimulated HDC transcription, but the mechanism appears to be indirect.
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PMID:Gastrin regulates the human histidine decarboxylase promoter through an AP-1-dependent mechanism. 914 14

Oxidant stress is thought to play a role in the pathogenesis of many gastric disorders. We have recently reported that histidine decarboxylase (HDC) promoter activity is stimulated by gastrin through a protein kinase C- and extracellular signal-regulating kinase (ERK)-dependent pathway in gastric cancer (AGS-B) cells, and this transcriptional response is mediated by a downstream cis-acting element, the gastrin response element (GAS-RE). To study the mechanism through which oxidant stress affects gastric cells, we examined the effects of hydrogen peroxide (H2O2) on HDC promoter activity and intracellular signaling in AGS-B cells. H2O2 (10 mM) specifically activated the HDC promoter 10-12-fold, and this activation was blocked by both mannitol and N-acetylcysteine. Hydrogen peroxide treatment of AGS-B cells increased the phosphorylation and kinase activity of ERK-1 and ERK-2, but did not affect Jun kinase tyrosine phosphorylation or kinase activity. In addition, treatment of AGS-B cells with H2O2 resulted in increased c-fos/c-jun mRNA expression and AP-1 activity, and also led to increased phosphorylation of epidermal growth factor receptor (EGFR) and Shc. H2O2-dependent stimulation of HDC promoter activity was completely inhibited by kinase-deficient ERKs, dominant-negative (N17 and N15) Ras, and dominant-negative Raf, and partially blocked by a dominant-negative EGFR mutant. In contrast, protein kinase C blockade did not inhibit H2O2-dependent induction of the HDC promoter. Finally, deletion analysis demonstrated that the H2O2 response element could be mapped to the GAS-RE (nucleotides 2 to 24) of the basal HDC promoter. Overall, these studies suggest that oxidant stress activates the HDC promoter through the GAS-RE, and through an Ras-, Raf-, and ERK-dependent pathway at least partially involving the EGFR.
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PMID:Oxidative stress activates the human histidine decarboxylase promoter in AGS gastric cancer cells. 972 30

UCN-01, a protein kinase C/cyclin-dependent kinase inhibitor, suppressed thymidylate synthase (TS) protein expression in a dose-dependent manner with near complete suppression at 1 microM after a 24-h exposure in human gastric cancer cell line SK-GT5. Other protein kinase C/cyclin-dependent kinase inhibitors, including flavopiridol and safingol, had a similar effect on TS protein expression, but to a lesser degree. Moreover, UCN-01 repressed the induction of TS after 5-fluorouracil (FU) exposure by 90-95% and significantly enhanced the induction of apoptosis by FU from 4-8% with either FU or UCN-01 alone to 46+/-1% (P < 0.005 versus either single drug, reverse sequence, or the combination) when UCN-01 was given after FU. The effect of UCN-01 on TS was associated with a dose-dependent suppression of the E2F-1 protein, a transcriptional activator of TS. Northern blot analysis revealed that TS mRNA levels decreased gradually as the concentration of UCN-01 increased, but that E2F-1 mRNA levels remained relatively unchanged. UCN-01 may provide a novel way to enhance cellular sensitivity toward FU by means of suppressing TS expression mediated mainly by down-regulation of E2F-1.
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PMID:UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in a sequence-dependent manner. 974 40


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