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)

To evaluate the mechanisms of T-cell dysfunction in patients with gastric cancer, we investigated the caspase activity of T cells, the induction of spontaneous T-cell apoptosis, the expression of T-cell receptor (TCR) zeta molecules, and the ability of T cells to produce cytokines in peripheral blood lymphocytes from patients (n = 22) and healthy controls (n = 14). The caspase-3 activity of T cells was studied as the protease activity of caspase-3 using the cell-permeable substrate of PhiPhiLux G1D2. Flow cytometric analysis was performed with triple staining by annexin V-FITC, propidium iodide, and CD3-R-phycoerythrin-Cy5 for the detection of T-cell apoptosis and with intracellular staining using permeabilized cells for the expression of TCR-zeta molecules. IFN-gamma and tumor necrosis factor alpha production from T cells was evaluated in response to anti-CD3 stimulation. Caspase-3 activity of peripheral blood T cells from patients with advanced disease was significantly increased compared with that from controls [15.5 +/- 3.6 mean fluorescence intensity (MFI) versus 11.5 +/- 3.3 MFI; P = 0.0068]. Parallel to this, the apoptosis of peripheral blood T cells from patients with advanced disease was significantly higher than for those from controls (16.5 +/- 15.5% versus 4.8 +/- 2.7%; P = 0.010). Furthermore, the expression of TCR-zeta molecules in patients with advanced disease was significantly decreased in comparison with that of the controls (41.0 +/- 13.9 MFI versus 56.7 +/- 16.3 MFI; P = 0.014), and this decreased expression coexisted with impaired IFN-gamma (42.4 +/- 43.2 pg/ml versus 1,757.4 +/- 2449.0 pg/ml; P = 0.031) and tumor necrosis factor alpha (682.6 +/- 519.3 pg/ml versus 1,686.0 +/- 1,533.7 pg/ml; P = 0.041) production of T cells. Thus, peripheral blood T cells from gastric cancer patients simultaneously exhibit an elevated caspase-3 activity, an increased degree of T-cell apoptosis, a down-regulation of TCR-zeta molecules, and impaired cytokine production. These observations suggest that induction of T-cell apoptosis coexisting with a down-regulation of TCR-zeta molecules may be responsible for T-cell dysfunction in patients with gastric cancer.
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PMID:Elevated caspase-3 activity in peripheral blood T cells coexists with increased degree of T-cell apoptosis and down-regulation of TCR zeta molecules in patients with gastric cancer. 1120 21

In this study, we aimed to determine the growth inhibition and the induction of apoptotic cell death brought about by the herb Anemarrhena asphodeloides Bunge in gastric cancer cell lines, and to clarify the mechanism of this apoptosis. Water-soluble ingredients of A. asphodeloides, and the gastric cancer cell lines, MKN45 and KATO-III, were used in vitro. Growth inhibition, induction of cell death, morphological features, the presence of DNA ladders, increases in caspase-3-like activity, the effects of a caspase-3 inhibitor on apoptotic cell death, and the release of cytochrome c by A. asphodeloides were analyzed. A. asphodeloides inhibited the growth and decreased the viability of the gastric cancer cell lines. The viability of normal skin fibroblasts in the presence of low concentrations of A. asphodeloides was higher than that of gastric cancer cells. Apoptotic bodies and DNA ladders were observed to be induced in MKN45 and KATO-III by A. asphodeloides. The caspase 3 inhibitor, Ac-DEVD-CHO, inhibited the apoptotic cell death of gastric cancer cells induced by A. asphodeloides. The caspase 3-like activity in MKN45 and KATO-III cells increased after the addition of A. asphodeloides. Cytochrome c was released from mitochondria into the cytosol 8 h after the addition of A. asphodeloides, and reached a peak at 16 h. The peak of cytochrome c release was earlier than that of caspase 3-like activity. We concluded that A. asphodeloides inhibited the growth of the gastric cancer cell lines MKN45 and KATO-III and induced apoptosis. The apoptosis of MKN45 and KATO-III cells induced by A. asphodeloides was associated with the release of cytochrome c from the mitochondria, followed by an increase in caspase 3-like activity.
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PMID:Growth inhibition and apoptosis of gastric cancer cell lines by Anemarrhena asphodeloides Bunge. 1122 75

Phorbol 12-myristate 13-acetate (PMA) rapidly induced cell death in SNU-16 gastric adenocarcinoma cells. DNA ladder formation and caspase-3/CPP32 activation were observed in PMA treated cells indicating that PMA induces apoptosis. z-DEVD-fmk, specific inhibitor of caspase-3/CPP32, inhibited the induction of apoptosis by PMA, demonstrating that caspase/CPP32 are critically involved in PMA-induced apoptosis. The serine protein inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride effectively blocked apoptosis, and also prevented caspase-3/CPP32 activation. Go6983, a specific inhibitor of PKC, almost completely suppressed apoptosis and caspase-3/CPP32 activation. Furthermore, 1,2-dihexanoyl-sn-glycerol, an endogenous activator of PKC, induced apoptosis detected by DNA fragmentation and Hoechst 33258 nuclear staining. From these results, we conclude that PMA is not only a tumor promoter, but can also induce apoptosis in gastric cancer cells. PMA-induced apoptosis appears to be mediated through activation of protein kinase C, and the activation of serine protease(s) and caspase-3/CPP32 may be the molecular mechanisms by which PMA induces apoptosis.
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PMID:Protein kinase C activation by PMA rapidly induces apoptosis through caspase-3/CPP32 and serine protease(s) in a gastric cancer cell line. 1129 59

Although TGF-beta1, a growth inhibitor, is known to also induce apoptosis, the molecular mechanism of this apoptosis is largely undefined. Here, we identify the mechanism of TGF-beta1-induced apoptosis in SNU-16 human gastric cancer cells. Cell cycle and TUNEL analysis showed that, upon TGF-beta1 treatment, cells were initially arrested at the G1 phase and then driven into apoptosis. Of note, caspase-3 was activated in accordance with TGF-beta1-induced G1 arrest. Activated caspase-3 is targeted to cleave p21(cip1), p27(kip1), and Rb, which play important roles in TGF-beta-induced G1 arrest, into inactive fragments. Subsequently, Cdk2 was aberrantly activated due to the cleavage of p21 and p27. We found that the inhibition of Cdk2 activity efficiently blocks TGF-beta1-induced apoptosis, whereas it did not prevent caspase-3 activation or the subsequent cleavage of target proteins. In contrast, the suppression of caspase-3 activity inhibited the cleavage of target proteins, the activation of Cdk2, and the induction of apoptosis. Taken together, our results suggest that activation of caspase-3 by TGF-beta1 may initiate the conversion from G1 cell cycle arrest to apoptosis via the cleavage of p21, p27 and Rb, which in turn causes Cdk2 activation and, most significantly, Cdk2 activation as a downstream effector of caspase is a critical step for the execution of TGF-beta1-induced apoptosis.
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PMID:Caspase-mediated Cdk2 activation is a critical step to execute transforming growth factor-beta1-induced apoptosis in human gastric cancer cells. 1131 70

The ubiquitin-proteasome pathway plays a critical role in the degradation of cellular proteins and cell cycle control. Dysregulating the degradation of such proteins should have profound effects on tumor growth and causes cells to undergo apoptosis. The aims of this study are to evaluate the ubiquitin-proteasome pathway in gastric cancer and the potential role of pharmacological inhibition of proteasome on induction of apoptosis in gastric cancer cells. Gastric cancer cell lines AGS (p53 wild-type) and MKN-28 (p53 mutant) were treated with proteasome inhibitor MG132. The results showed that MG132 inhibited cell proliferation in AGS and MKN-28 cells in a time- and dose-dependent manner. The inhibition of cell proliferation was caused by apoptosis which was also time- and dose-dependent. AGS cells were more responsive to MG132 than MKN-28 cells. Induction of apoptosis was preceded by the activation of caspase-3, as measured by a colorimetric caspase-3 cellular activity and Western blotting of the cleavage of caspase-3 and its substrate PARP. Activation of caspase-7 was also exhibited. In addition, z-VAD-fmk, a broad spectrum caspase inhibitor, reversed apoptosis induced by MG132 in AGS and MKN28 cells. Although z-DEVD-fmk, a specific caspase-3 inhibitor, suppressed MG132-induced apoptosis in MKN28 cells, it only partially rescued the apoptotic effect in AGS cells. Caspase-3 activation was the result of release of cytochrome c from mitochondria into the cytosol, as a consequence of upregulation of bax. There were overexpressions of all the proteasome-related proteins p53, p21(waf1) and p27(kip1) at 4 hr after proteasome inhibition which was identified by the accumulation of ubiquitin-tagged proteins. This was accompanied by accumulation of cells at G(1) phase. Our present study suggests that inhibition of proteasome function in gastric cancer cells induces apoptosis and proteasomal inhibitors have potential use as novel anticancer drugs in gastric cancer.
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PMID:Inhibition of proteasome function induced apoptosis in gastric cancer. 1147 51

Aspirin- and non-steroidal anti-inflammatory drug (NSAID)-induced apoptosis is one of the important mechanisms for their anti-tumour effect in gastric cancer. We aimed at determining the role of bcl-2 family proteins and caspases in the apoptotic process. Gastric cancer cell lines AGS (wild-type p53) and MKN-28 (mutant p53) were used. Cell proliferation was measured by MTT assay. Apoptosis was determined by acridine orange staining. Protein expressions were determined by western blotting. Aspirin and indomethacin inhibited cell proliferation and induced apoptosis in both cells. AGS cells were more sensitive compared with MKN-28 cells. The pro-apoptotic proteins bax and bak were overexpressed after treatment, while the protein level of bcl-2 remained unchanged. Apoptosis was accompanied by an increase in caspase-3 activity and cleavage of caspase-3 and poly(ADP-ribose) polymerase. Inhibition of caspase-3 rescued aspirin-induced apoptosis. Our results suggest that one of the major pathways which mediates the anti-tumour response of aspirin and indomethacin in gastric cancer cells is through up-regulation of bax and bak and activation of caspase-3. Bax and bak are important in the chemoprevention of gastric cancer.
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PMID:Non-steroidal anti-inflammatory drugs induce apoptosis in gastric cancer cells through up-regulation of bax and bak. 1153 60

The cytotoxin-associated gene (cagA) and vacuolating cytotoxin (Vac) production have been reported to be major virulence factors of Helicobacter pylori. However, there have been some disputes regarding the correlation between these virulence factors and clinical outcomes. We evaluated whether the cagA-positive genotype and Vac production might be correlated with various gastroduodenal diseases in Korea and whether this correlation could be due to differences in proinflammatory cytokine gene expression and apoptosis of gastric epithelial cells in vitro. The presence of the cagA gene was examined by the polymerase chain reaction (PCR), and Vac production was detected using the bacterial culture supernatant and HeLa cells after H. pylori was isolated from Korean patients. Gastric epithelial cells were infected with cagA+Vac+, cagA+Vac-, or cagA-Vac- strains, after which cytokine gene expression was evaluated, using quantitative reverse transcription (RT)-PCR. Apoptosis and caspase-3 activation were measured in H. pylori-infected gastric epithelial cells. There was no significant correlation between the presence of these virulence factors in H. pylori isolates and peptic ulcer or gastric cancer. Upregulation of cytokine gene expression, including that of interleukin (IL)-1alpha, IL-8, granulocyte macrophage colony-stimulating factor (GM-CSF), and monocyte chemotactic protein (MCP)-1, as well as apoptosis and caspase-3 activation, were similar in infections with cagA-positive and cagA-negative strains, but were not correlated with the production of Vac. These results suggest that the lack of correlation between virulence factors of isolated H. pylori strains and serious gastroduodenal disease entities in Korea may be due to the similar capacity for proinflammatory cytokine gene expression and apoptosis caused by infection with each of the H. pylori strains.
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PMID:Virulence factors of Helicobacter pylori in Korean isolates do not influence proinflammatory cytokine gene expression and apoptosis in human gastric epithelial cells, nor do these factors influence the clinical outcome. 1157 34

Although gastric cancer formation with H. pylori in Mongolian gerbils was recently reported, the same inoculation procedure did not result in cancer formation in other animals such as mice. Disturbed regulation of apoptosis and cell proliferation are known to link the multistep process of carcinogenesis. The present study is designed to examine the level of gastric epithelial cell apoptosis in Mongolian gerbils colonized with the H. pylori (Sydney strain: SS1) in comparison with that in mice. Mice (C57BL/6) and Mongolian gerbils were orally inoculated with SS1 and the stomachs were examined 9 and 18 months later. MPO activity increased persistently in gerbils, but increased transiently in mice. While the levels of DNA fragmentation, caspase-3 activity, and the number of TUNEL-positive cells increased significantly in mice, such parameters were attenuated in gerbils. On the other hand, the number of PCNA-positive cells increased after SS1 inoculation only in Mongolian gerbils, suggesting the enhancement of cell turnover in H. pylori-colonized gerbils. In conclusion, the SS1-induced increase in gastric mucosal apoptosis observed in mice was attenuated significantly in Mongolian gerbils, suggesting the causative role for the higher incidence of gastric carcinogenesis in this animal.
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PMID:Attenuated apoptosis in H. pylori-colonized gastric mucosa of Mongolian gerbils in comparison with mice. 1183 40

Gastric cancer is one of the most common malignant tumors of the gastrointestinal tract. However, the molecular pathways involved in the regulation of gastric carcinogenesis are not completely elucidated. In the last decade, basic cancer research has been focused on the deregulation of apoptosis as a central event in the process of carcinogenesis. Caspase-3 and survivin are regulators of apoptosis and have been implicated in the development of gastric cancer. The aim of the present study was to compare the expression of mRNA and protein for survivin and caspase-3 in the gastric cancer and in the cancer margin with that in normal human gastric mucosa. Fifteen patients with advanced gastric cancer (all H. pylori-positive) and 15 matched control subjects with normal gastric mucosa were included in this study. The biospy specimens for histology and for molecular analyses were taken from gastric tumor, tumor surrounding gastric mucosa and in normal patients from the mucosa of antrum and corpus. Survivin mRNA expression was very weak, but detectable, in the normal gastric mucosa. However, at the protein level, no expression for survivin was detected in the normal gastric mucosa. In the biopsy specimens from tumor and surrounding gastric mucosa, a significant increase in survivin mRNA and protein expression was observed. The expression of survivin was higher in the tumor than in the tumor margin. The mRNA and protein expression of caspase-3 was detected in the gastric mucosa of normal subjects. In gastric cancer only the expression of procaspase-3 was observed, while the expression of active caspase-3 was completely undetectable. In the gastric mucosa surrounding gastric cancer, no gene and protein expression for caspase-3 was detected. We conclude that the changes in the level of caspase-3 and survivin play an important role in the transformation from normal gastric mucosa to gastric career.
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PMID:Expression of survivin and caspase-3 in gastric cancer. 1264 1

5-fluorouracil (5-FU) is used for the treatment of stomach and colon cancer, but many tumors are resistant to this chemotherapeutic agent. 5-FU induces apoptosis of several cancer cell lines, while some chemotherapeutic agents are known to activate the transcriptional factor NF-kappaB, which strongly suppresses apoptosis in vitro. In the present study, we investigated the relationship between activation of NF-kappaB and chemoresistance to 5-FU in human stomach cancer cell lines, NUGC3 (5-FU sensitive) and NUGC3/5FU/L (5-FU resistant). Treatment with 5-FU for 9-12 h caused activation of inducible NF-kappaB in NUGC3/5FU/L cells but not in NUGC3 cells. 5-FU also resulted in an increase in the number of TUNEL-positive cells and enhanced caspase-3 activity 3- to 5-fold in NUGC3 cells but not NUGC3/5FU/L cells. Moreover we also demonstrated that the inhibition of inducible NF-kappaB activation by using a NF-kappaB decoy could induce apoptosis and reduce chemoresistance against 5-FU. Our results suggest that 5-FU chemoresistance can be overcome by inhibition of inducible NF-kappaB activation, and that the use of the NF-kappaB decoy combined with 5-FU treatment is a new molecular and gene therapeutic strategy aimed at treatment of human stomach cancers resistant to 5-FU.
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PMID:Inhibition of inducible NF-kappaB activity reduces chemoresistance to 5-fluorouracil in human stomach cancer cell line. 1294 1


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