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)

Camptothecin, a topoisomerase I inhibitor, is a well-known anticancer drug. However, its mechanism has not been well studied in human gastric cancer cell lines. Camptothecin induced apoptotic cell death in human gastric cancer cell line AGS. Z-VAD-fmk, pan-caspase inhibitor, blocked apoptotic phenotypes induced by camptothecin suggesting that caspases are involved in camptothecin-induced cell death. An inhibitor of caspase-6 or -8 or -9 did not prevent cell death by camptothecin. Various protease inhibitors failed to prevent camptothecin-induced cell death. These results suggest that only few caspases are involved in camptothecin-induced cell death. Camptothecin induced phosphorylation of ERK1/2, JNK, and p38 MAPK, in a dose and time-dependent manner in AGS. Z-VAD-fmk did not affect MAPK signaling induced by camptothecin suggesting that caspase signaling occurs downstream of MAPK signaling. Blocking of p38 MAPK, but not ERK1/2, resulted in partial inhibition of cell death and PARP cleavage by camptothecin in AGS. Taken together, MAPK signaling is associated with apoptotic cell death by camptothecin.
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PMID:MAPK signaling is involved in camptothecin-induced cell death. 1252 Dec 96

Helicobacter pylori induces activation of mitogen-activated protein kinases (MAPKs). However, its effect on H. pylori-induced apoptosis has not been evaluated. Thus, we examined whether H. pylori-induced extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 MAPK activation affects gastric epithelial cell apoptosis and bcl-2 family gene expression, especially in relation to the cagA status of an H. pylori strain. In flow cytometric and oligonucleosome-bound DNA enzyme-linked immunosorbent assay analyses, infection with cagA(+) H. pylori strains induced gastric cancer cell apoptosis in AGS cells more prominently than infection with cagA mutants. Activation of ERK1/2 and p38 MAPKs was also more prominent in cagA(+) strains. Pretreatment with a MEK inhibitor (PD98059) inhibited ERK1/2 activation and increased H. pylori-induced apoptosis significantly. This increased apoptosis was accompanied by decreased antiapoptotic bcl-2 mRNA expression among bcl-2-related genes (bcl-2, bax, bak, mcl-1, and bcl-X(L/S)), and the effect was also more prominent in the cagA(+) strains. However, the alteration of bcl-2 gene expression was not accompanied by protein level changes. Inhibition of p38 using specific inhibitor SB203580 decreased H. pylori-induced apoptosis but resulted in little alteration of bcl-2-related gene expression. In conclusion, H. pylori-induced ERK1/2 activation, especially by the cagA(+) H. pylori strain, may play a protective role against gastric epithelial cell apoptosis partially through maintenance of bcl-2 gene expression.
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PMID:Effect of inhibition of extracellular signal-regulated kinase 1 and 2 pathway on apoptosis and bcl-2 expression in Helicobacter pylori-infected AGS cells. 1254 May 63

Both heme oxygenase-1 (HO-1) and p21(WAF1/Cip1) (p21) are involved in the pathogenesis of human cancer and their functions are closely associated with apoptosis. However, how these two molecules regulate apoptosis in human gastric cancer is unknown. In this study, we studied how HO-1 and p21 were regulated in two gastric cancer cell lines, MKN-45 with wild p53 and MKN-28 with mutant p53. The cells were treated with hemin and cadmium to induce HO-1. The result showed that HO-1 protein was significantly induced by hemin and cadmium in both cells tested. Following the HO-1 expression, p21 level was also markedly induced. The cells with increased HO-1 and p21 showed obviously resistantance to apoptotic stimuli. The levels of HO-1 and p21 induced were significantly inhibited by p38 mitogen-activated protein kinase (p38 MAPK) inhibitor (SB203580) and extracellular-regulated kinase (ERK) inhibitor (PD098059). Parallel to decreased HO-1 and p21 expression, the kinase inhibitors also significantly attenuated the resistance of the cells to apoptosis. The elevated HO-1 and p21 was further found to be associated with increase activity of the nuclear NF-kappaB and the inhibition of NF-kappaB led to the block of their induction. The elevated HO-1 and p21 were also demonstrated to be related to increased cellular inhibitor of caspase inbitory protein-2 (c-IAP2) and decreased caspapse-3 activity. It was noted that the above changes observed were not different between MKN-45 and MKN-28 cells, suggesting the functions of HO-1 and p21 were irrespective of the status of p53. In conclusion, we demonstrate that the resistance to apoptosis in gastric cancer cells with elevated HO-1 and p21 is independent of p53 status in a p38 MAPK- and ERK-mediated pathway with elevated c-IAP2 and decreased caspase-3 activity and that this pathway is sensitive to the inhibition of NF-kappaB.
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PMID:Upregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells. 1464 39

Helicobacter pylori is a Gram-negative microaerophilic bacterium that causes chronic gastritis, peptic ulcer, and gastric carcinoma. Interleukin-1beta (IL-1beta) is one of the potent proinflammatory cytokines elicited by H. pylori infection. We have evaluated the role of H. pylori lipopolysaccharide (LPS) as one of the mediators of IL-1beta release and dissected the signaling pathways leading to LPS-induced IL-1beta secretion. We demonstrate that both the NF-kappaB and the C/EBPbeta-binding elements of the IL-1beta promoter drive LPS-induced IL-1beta gene expression. NF-kappaB activation requires the classical TLR4-initiated signaling cascade leading to IkappaB phosphorylation as well as PI-3K/Rac1/p21-activated kinase (PAK) 1 signaling, whereas C/EBPbeta activation requires PI-3K/Akt/p38 mitogen-activated protein (MAP) kinase signaling. We observed a direct interaction between activated p38 MAP kinase and C/EBPbeta, suggesting that p38 MAPK is the immediate upstream kinase responsible for activating C/EBPbeta. Most important, we observed a role of Rac1/PAK1 signaling in activation of caspase-1, which is necessary for maturation of pro-IL-1beta. H. pylori LPS induced direct interaction between PAK1 and caspase-1, which was inhibited in cells transfected with dominant-negative Rac1. PAK1 immunoprecipitated from lysates of H. pylori LPS-challenged cells was able to phosphorylate recombinant caspase-1, but not its S376A mutant. LPS-induced caspase-1 activation was abrogated in cells transfected with caspase-1(S376A). Taken together, these results suggested a role of PAK1-induced phosphorylation of caspase-1 at Ser376 in activation of caspase-1. To the best of our knowledge our studies show for the first time that LPS-induced Rac1/PAK1 signaling leading to caspase-1 phosphorylation is crucial for caspase-1 activation. These studies also provide detailed insight into the regulation of IL-1beta gene expression by H. pylori LPS and are particularly important in the light of the observations that IL-1beta gene polymorphisms are associated with increased risk of H. pylori-associated gastric cancer.
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PMID:NF-kappaB- and C/EBPbeta-driven interleukin-1beta gene expression and PAK1-mediated caspase-1 activation play essential roles in interleukin-1beta release from Helicobacter pylori lipopolysaccharide-stimulated macrophages. 1556 13

In view of the continuing need for effective anticancer agents, and the association of diet with reduced cancer risk, edible plants are increasingly being considered as sources of anticancer drugs. Hibiscus sabdariffa Linne (Malvaceae), an attractive plant believed to be native to Africa, is cultivated in the Sudan and Eastern Taiwan. Polyphenols had been demonstrated previously to possess antioxidative and antitumor promoting effects. In this study, investigations were conducted to examine the mechanism of the anticancer activity of H. sabdariffa L., Hibiscus polyphenol-rich extracts (HPE). Using HPLC assay, HPE was demonstrated to contain various polyphenols. HPE induced cell death of eight kinds of cell lines in a concentration-dependent manner. Among them human gastric carcinoma (AGS) cells were the most susceptible to HPE (0.95 mg/mL HPE inhibited its growth by 50%). Our results revealed that AGS cells underwent DNA fragmentation, and had an increase in the distribution of hypodiploid phase (apoptotic peak, 52.36%) after a 24-h treatment with HPE (2.0 mg/mL). This effect of HPE in AGS cells might be mediated via p53 signaling and p38 MAPK/FasL cascade pathway, as demonstrated by an increase in the phosphorylation of p53 and the usage of a specific p38 inhibitor, SB203580. Thus, our data present the first evidence of HPE as an apoptosis inducer in AGS cells and these findings may open interesting perspectives to the strategy in human gastric cancer treatment.
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PMID:Hibiscus polyphenol-rich extract induces apoptosis in human gastric carcinoma cells via p53 phosphorylation and p38 MAPK/FasL cascade pathway. 1579 51

CKBM is an herbal formula composed of five Chinese medicinal herbs (Panax ginseng, Schisandra chinensis, Fructus crataegi, Ziziphus jujube and Glycine Max) supplemented with processed Saccharomyces cerevisiae. Previous studies have demonstrated that CKBM is capable of triggering the release of IL-6 and TNFalpha from human peripheral blood mononuclear cells, and its anti-tumorigenic activity has been demonstrated in nude mice with gastric cancer. In this report, we utilized the THP-1 monocytic cell line as a cellular model to investigate how CKBM regulates the intracellular signaling of monocytes and the subsequent release of the produced cytokines. In terms of mitogen-activated protein kinase (MAPK) cascades, CKBM (20%) had no significant effect on ERK, but was linked to an inhibitory effect on JNK and a stimulatory effect on p38 MAPK. The differential responsiveness of JNK and p38 was dependent on the duration of treatment, as well as on the dosage of CKBM. Treatment of CKBM alone induced the release of IL-10 and IFNgamma, but not IL-1beta, IL-4, IL-6 and TNFbeta, while increase of intracellular Ca2+ concentration by A23187 triggered the release of IL-10 only. Interestingly, A23187 synergized with the activities of CKBM-treated THP-1 cells in terms of IL-1beta and IFNgamma production, while the IL-10 production showed no synergistic relationship between CKBM and A23187. This A23187-induced synergism was associated with a dose-dependent character towards CKBM administration. In view of the intracellular Ca2+ elevation during monocyte activation, our results suggest that CKBM can serve as a promoting agent for modulating the functions of monocytes.
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PMID:Immuno-regulatory effects of CKBM on the activities of mitogen-activated protein kinases and the release of cytokines in THP-1 monocytic cells. 1614 32

Cyclooxygenase-2 (COX-2) plays a crucial role in Helicobacter pylori-associated gastric cancer. In this study, we report that H. pylori-induced COX-2 expression enhances the cancer cell invasion and angiogenesis via TLR2 and TLR9, which can be attenuated by the specific COX-2 inhibitor NS398 or celecoxib. The cAMP response element (CRE) and AP1 sites, but not kappaB on the COX-2 promoter, are involved in MAPKs-regulated COX-2 expression. Differential bindings of the CREB-1, ATF-2, c-jun to the CRE site, and the c-fos, c-jun, ATF-2 to the AP1 site are demonstrated by DNA affinity protein-binding, supershift, and chromatin immunoprecipitation assays. Activations of these transcription factors were attenuated by different MAPKs inhibitors. The mutants of TLR2, TLR9, or MAPKs inhibited H. pylori-induced COX-2 promoter, CRE, and AP-1 activities. MAPKs inhibitors attenuated the H. pylori-induced COX-2 mRNA and protein expressions. These results indicate that H. pylori acts through TLR2 and TLR9 to activate MAPKs, especially p38, and their downstream transcription factors (CREB-1, ATF-2, c-jun, and c-fos), resulting in the activations of CRE and AP-1 on the COX-2 promoter. These intracellular networks drive the COX-2-dependent PGE2 release and contribute to cell invasion and angiogenesis.
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PMID:Helicobacter pylori-Induced invasion and angiogenesis of gastric cells is mediated by cyclooxygenase-2 induction through TLR2/TLR9 and promoter regulation. 1633 64

Cyclooxygenase-2 (COX-2) expression is a marker of poor prognosis in gastric cancer patients, and its inhibition suppresses gastric tumorigenesis in experimental animal models. The mechanism that leads to COX-2 overexpression in this tumor type is unknown. We have now shown that inhibition of phosphatidylinositol 3-kinase by LY294002 suppresses both basal and phorbol myristate acetate-induced COX-2 expression in TMK-1 and MKN-28 gastric cancer cells. Furthermore, inhibition of glycogen synthase kinase-3beta (GSK-3beta) by SB415286 induced expression of COX-2 mRNA and protein as well as the enzyme activity in the gastric cancer cells. The effect of SB415286 was confirmed by the use of two additional GSK-3beta inhibitors, lithium chloride and SB216763. SB415286 had a modest 1.6-fold stimulatory effect on a 2-kb COX-2 promoter reporter construct, but more importantly, it was shown to block the decay of COX-2 mRNA. In contrast to modulation of phosphatidylinositol 3-kinase/Akt/GSK-3beta pathway, inhibitors of mitogen-activated protein kinases (MEK 1/2, p38, JNK) or the mammalian target of rapamycin did not alter COX-2 expression in gastric cancer cells. Our data show that inhibition of GSK-3beta stimulates COX-2 expression in gastric cancer cells, which seems to be primarily facilitated via an increase in mRNA stability and to a lesser extent through enhanced transcription.
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PMID:Expression of cyclooxygenase-2 is regulated by glycogen synthase kinase-3beta in gastric cancer cells. 1637 52

The regulatory mechanisms for the proliferation and the particular invasive phenotypes of stomach cancers are not still fully understood. Up-regulations of hepatocytes growth factor (HGF), its receptor (c-Met), and urokinase-type plasminogen activator (uPA) are correlated with the development and metastasis of cancers. In order to investigate roles of HGF/c-Met signaling in tumor progression and metastasis in stomach cancers, we determined effects of a specific MEK1 inhibitor (PD098059) and a p38 kinase inhibitor (SB203580) on HGF-mediated cell proliferation and uPA expression in stomach cancer cell lines (NUGC-3 and MKN-28). HGF treatment induced the phosphorylations of ERK and p38 kinase in time- and dose- dependent manners. Pre-treatment with PD098059 reduced HGF-mediated cell proliferation and uPA secretion. In contrast, SB203580 pre-treatment enhanced cell proliferation and uPA secretion due to induction of ERK phosphorylation. Stable expression of dominant negative-MEK1 in NUGC-3 cells showed a decrease in HGF-mediated uPA secretion. These results suggest that interaction of a MEK/ERK and a p38 kinase might play an important role in proliferation and invasiveness of stomach cancer cells.
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PMID:Regulation of hepatocyte growth factor-mediated urokinase plasminogen activator secretion by MEK/ERK activation in human stomach cancer cell lines. 1652 May 50

Cisplatin (CDDP) is a DNA damaging agent and is widely used for treating cancer. While the role of p53 in CDDP-induced cell death has been stressed, evidence exists that CDDP can also kill p53-mutated cells. To investigate the latter mechanism, we performed a comparative study using three different human cell types, SNU-16 (a stomach cancer cell-line), U937 (a leukemic cell-line) and 293T (a kidney fibroblast cell-line), which are defective in terms of p53 activation. A focus was placed on Bcl-2 family proteins, reactive oxygen species (ROS), and mitogen-activated protein kinases. Our results suggest that the ability of CDDP to kill these cells can be mediated by JNK, p38 MAPK and ROS, but not by ERK. It was also found that CDDP can increase the ratio of pro-apoptotic/pro-survival Bcl-2 members. While the importance of these components was found to depend on cell type, JNK was commonly involved in the deaths of all cell types examined. Therefore, the JNK pathway appears to be an ideal target for the modulation of the lethal action of CDDP in multiple types of p53-mutated cells.
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PMID:Cellular components involved in the cell death induced by cisplatin in the absence of p53 activation. 1659 82


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