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)

Apoptois is an important determinant in the sensitivity to chemotherapeutic agents in gastric cancer cells. In this study, we examined whether the introduction of the bax gene into MKN45 gastric cancer cells could enhance the sensitivity to chemotherapeutic agents in association with apoptosis. Apoptosis in the bax-transfected gastric cancer cells was enhanced following the treatment of various chemotherapeutic agents including adriamycin (ADM), cisplatin (CDDP), etoposide (VP-16) and taxotere (TXT) as compared to those of neo gene-transfected cells. The enhancement of apoptosis was coincident with the increase of sensitivity in the ratio of IC50 value, that was 1.3-fold in ADM, 4.4-fold in CDDP, 4.6-fold in VP-16 and 2.5-fold in TXT, respectively. Further, the enhancement of apoptosis in the bax-transfected gastric cancer cells was associated with the activation of c-Jun N-terminal kinase 1 (JNK 1) and caspase 3 (CPP32). The increases of sensitivities to these agents in the bax-transfected cells were also demonstrated in in vivo experiments using the tumor cells transplanted into nude mice. The tumor growth in the bax-transfected cells was significantly suppressed following the treatment of CDDP or VP-16 compared to that of neo-transfected cells (p < 0.05). These results indicated that, the bax gene might play a critical role in determination of sensitivity to chemotherapeutic agent in gastric cancer cells in vivo, and that the activation of JNK 1 and CPP32 might be involved in the signal transduction pathways leading to apoptosis.
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PMID:Enhancement of chemotherapeutic agents induced-apoptosis associated with activation of c-Jun N-terminal kinase 1 and caspase 3 (CPP32) in bax-transfected gastric cancer cells. 1076 93

Apoptosis plays a critical role in maintaining genomic integrity by selectively removing the most heavily damaged cells from the population. Reactive oxygen species (ROS) and certain inflammatory cytokines are always elevated during the human carcinogenic process. However, the biological significance of the interplay between ROS and inflammatory cytokine remains elusive. This study demonstrates that interleukin-6 (IL-6) effectively protects gastric cancer cells from the apoptosis induced by hydrogen peroxide (H(2)O(2)). The cell death signaling JNK pathway elicited by H(2)O(2) is also inhibited by IL-6. We further found that Mcl-1, but not other Bcl-2 family members, was up-regulated by IL-6, by a substantial level over 24 h. We further transfected a mcl-1 expression vector, pCMV-mcl-1, into the AGS cells, and successfully obtained several mcl-1-overexpressing clones. Flow cytometric analysis shows that these mcl-1-overexpressing AGS cells are more resistant to the apoptosis induced by H(2)O(2) when compared with the neo control AGS cells. Consistently, the activation of the JNK pathway induced by H(2)O(2) is also blocked in mcl-1-overexpressed cells. These results indicate that the anti-apoptotic effect of IL-6 is, at least in part, due to the up-regulation of mcl-1. To our surprise, either IL-6 exposure or mcl-1 overexpression fails to reduce the level of intracellular peroxides in the AGS cells triggered by H(2)O(2). This study also determined the level of 8-hydroxydeoxyguanosine (8-OH-dGua), an indicator for oxidative DNA lesions in IL-6-treated or mcl-1-overexpressed AGS cells after treatment with H(2)O(2). Notably, our results indicate that a majority of the 8-OH-dGua is efficiently removed in the AGS cells without IL-6 treatment, whereas only approximately 50% of the 8-OH-dGua was repaired in the IL-6-treated AGS cells after 24 h. Similarly, approximately 60-70% of the 8-OH-dGua also failed to repair and was retained in the genomic DNA of the mcl-1 transfectants. Results in this study provide a novel mechanism by which up-regulation of the Mcl-1 protein by IL-6 may enhance the susceptibility to H(2)O(2)-induced oxidative DNA lesions by overriding apoptosis.
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PMID:IL-6 inhibits apoptosis and retains oxidative DNA lesions in human gastric cancer AGS cells through up-regulation of anti-apoptotic gene mcl-1. 1175 24

Secreted-type glycoprotein WNTs bind to seven-transmembrane-type WNT receptors encoded by Frizzled genes (FZD1-FZD10) to transduce signals to the beta-catenin--TCF pathway, the JNK pathway, or the Ca(2+)-releasing pathway. Wrch1 gene is a down-stream target gene of Wnt1 in C57MG cells, and encodes a Cdc42-related GTPase with the potential to activate the JNK pathway. Here, we isolated human WRCH1 cDNAs (accession no. AB074878) from gastric cancer cell lines OKAJIMA, MKN7, MKN28, MKN45, MKN74, and KATO-III, all of which showed a nucleotide substitution (343 C-->T) without amino-acid substitution compared with WRCH1 cDNA isolated by another group. WRCH1 gene, consisting of at least 3 exons, was mapped to human chromosome 1q42.11-q42.3 by using bioinformatics. WRCH1 mRNA was more highly expressed in corpus callosum, hippocampus, cerebral cortex, and also in several parts within adult brain than in other normal tissues including stomach, pancreas, and placenta. Amounts of WRCH1 mRNA in 40 human cancer cell lines were lower than that in normal stomach, pancreas, or placenta. WRCH1 mRNA was significantly up-regulated in 4 cases of primary kidney tumors, 1 case each of primary colon, gastric, breast, ovarian, and uterus cancer. On the other hand, WRCH1 mRNA was significantly down-regulated in 6 cases of colon tumors, 2 cases of primary kidney cancer and breast cancer. Expression of WRCH1 mRNA was down-regulated by beta-estradiol in MCF-7 cells. This is the first report on comprehensive expression analyses on WRCH1 mRNA.
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PMID:Expression of WRCH1 in human cancer and down-regulation of WRCH1 by beta-estradiol in MCF-7 cells. 1189 24

WNT signals are transduced to the JNK pathway, the Ca2+-releasing pathway, or the beta-catenin - TCF pathway through seven-transmembrane-type WNT receptors encoded by Frizzled genes (FZD1-FZD10). WRCH1/ARHV and CDC42 are potentially implicated in the WNT-JNK pathway. Here, WRCH2/ARHV cDNAs were isolated by using bioinformatics and cDNA-PCR. WRCH2 gene, consisting of at least 3 exons, encoded a 236-amino-acid protein with proline-rich domain and GTPase domain. WRCH2 was homologous to WRCH1 (55.4% total-amino-acid identity) and CDC42 (43.5% total-amino-acid identity). WRCH2 gene was located on human chromosome 15q15, which is one of fragile sites in the human genome. A single nucleotide substitution (632 Gright curved arrow A) was identified between WRCH2 cDNA and human genome draft sequences, which resulted in Arg177Lys amino-acid substitution. WRCH2 mRNA was relatively highly expressed in pancreas, placenta, and fetal brain. WRCH2 mRNA was over-expressed in TMK1 (gastric cancer), Hs700T (pancreatic cancer), HeLa S3 (cervical cancer), and A549 (lung cancer). WRCH2 mRNA was moderately expressed in MKN74, MKN45, MKN28, KATO-III (gastric cancer), HL-60 (pro-myelocytic leukemia), Raji (Burkitt's lymphoma), and SW480 (colorectal cancer). WRCH2 mRNA was up-regulated in 3 out of 8 cases of primary gastric cancer. Because Wrch1 can activate PAK1 and JNK1, and induce filopodium formation and stress fiber dissolution, over-expression of WRCH2 mRNA in human cancer cells might also lead to more malignant phenotype.
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PMID:Molecular cloning and characterization of WRCH2 on human chromosome 15q15. 1195 92

WNT signaling pathway is implicated in carcinogenesis and embryogenesis. WNT signal is transduced to the beta-catenin - TCF pathway, the JNK pathway, or the Ca2+-releasing pathway through seven-transmembrane-type WNT receptors encoded by Frizzled (FZD) genes. Xenopus Strabismus (Stbm) is a tetra-spanning transmembrane protein interacting with Dishevelled, and is a negative regulator of the WNT - beta-catenin - TCF signaling pathway. STB1/KIAA1215/VANGL2 is a human orthologue of Xenopus Stbm (90.6% total-amino-acid identity). Here, STB2/VANGL1 gene fragments were identified in human genome draft sequences by using bioinformatics, and STB2 cDNAs were isolated by using cDNA-PCR. STB2 gene consisted of at lest 7 exons, and encoded a 524-amino-acid protein with 4 transmembrane domains and the C-terminal Ser/Thr-X-Val motif. Human STB2 was homologous to human STB1 (73.1% total-amino-acid identity) and Xenopus Stbm (72.7% total-amino-acid identity). STB2 gene was clustered with Calsequestrin 2 (CASQ2) gene in tail-to-tail manner (interval less than 5.0 kb), and CASQ2 gene is mapped to human chromosome 1p11-p13.3 or linked to human chromosome 1p13-p21. STB2 mRNAs of 4.8- and 6.8-kb in size were expressed almost ubiquitously in various normal tissues. STB2 mRNA was significantly up-regulated in gastric cancer cell lines MKN28, MKN74, pancreatic cancer cell lines BxPC-3, PSN-1 and Hs766T. On the other hand, STB2 mRNA was significantly down-regulated in a pancreatic cancer cell line AsPC-1. This is the first report on molecular cloning and characterization of STB2.
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PMID:Molecular cloning and characterization of Strabismus 2 (STB2). 1195 95

WNT signal is transduced to the beta-catenin - TCF pathway, the JNK pathway, or the Ca2+-releasing pathway through seven-transmembrane-type WNT receptors encoded by Frizzled genes (FZD1-FZD10). We have previously cloned and characterized human WNT2B/WNT13, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT10A, WNT10B, WNT11, WNT14, and WNT14B/WNT15 by using bioinformatics, cDNA-library screening, and cDNA-PCR. Here, we investigated expression of human WNT5A mRNA in various normal tissues, 66 primary tumors derived from various tissues, and 15 human cancer cell lines. WNT5A mRNA was relatively highly expressed in salivary gland, bladder, uterus, placenta, and fetal kidney. Up-regulation of WNT5A mRNA was detected in 5 out of 8 cases of primary gastric cancer, 5 out of 18 cases of primary colorectal tumors, and in 2 out of 7 cases of primary uterus tumors by using matched tumor/normal expression array analysis. Up-regulation of WNT5A mRNA was also detected in 7 out of 10 other cases of primary gastric cancer by using cDNA-PCR. Although low-level expression of WNT5A mRNA was detected in gastric cancer cell line MKN45, WNT5A mRNA was almost undetectable in gastric cancer cell lines OKAJIMA, TMK1, MKN7, MKN28, MKN74, and KATO-III. Compared with frequent up-regulation of WNT5A mRNA in primary gastric cancer, expression levels of WNT5A mRNA in 7 gastric cancer cell lines were significantly lower than that in normal stomach. Frequent up-regulation of WNT5A mRNA in human primary gastric cancer might be due to cancer-stromal interaction.
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PMID:Frequent up-regulation of WNT5A mRNA in primary gastric cancer. 1195 59

WNT signals are transduced through seven-transmembrane-type WNT receptors encoded by Frizzled (FZD) genes to the beta-catenin - TCF pathway, the JNK pathway or the Ca2+-releasing pathway. WNT signaling molecules are potent targets for diagnosis of cancer (susceptibility, metastasis, and prognosis), for prevention and treatment of cancer, and for regenerative medicine or tissue engineering. We have so far cloned and characterized human WNT signaling molecules WNT2B/WNT13, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT10A, WNT10B, WNT11, WNT14, WNT14B/WNT15, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD10, FRAT1, FRAT2, NKD1, NKD2, VANGL1/STB2, ARHU/WRCH1, ARHV/WRCH2, GIPC2, GIPC3, betaTRCP2/FBXW1B, SOX17, and TCF-3 using bioinformatics, cDNA-library screening, and cDNA-PCR. Here, expression of WNT7A in human normal tissues and cancer, and regulation of WNT7A and WNT7B in human cancer were investigated. WNT7A was highly expressed in fetal lung, adult testis, lymph node, and peripheral blood leukocytes. WNT7A was relatively highly expressed in temporal lobe, occipital lobe, parietal lobe, paracentral gyrus of cerebral cortex, caudate nucleus, hippocampus, medulla oblongata and putamen within adult brain. WNT7A was highly expressed in SW480 (colorectal cancer), BxPC-3 and Hs766T (pancreatic cancer), and was also expressed in MKN7 and MKN45 (gastric cancer). WNT7B rather than WNT7A was expressed in MCF-7 (breast cancer) and NT2 (embryonal tumor). beta-estradiol did not affect expression levels of WNT7A and WNT7B in MCF-7 cells. WNT7B, but not WNT7A, was slightly up-regulated by all-trans retinoic acid in NT2 cells.
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PMID:Expression of WNT7A in human normal tissues and cancer, and regulation of WNT7A and WNT7B in human cancer. 1223 32

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

To determine a cellular factor supporting the survival of gastric cancer cells, a comparative study was performed using two human adenocarcinoma cell lines, SNU-16 and SNU-620. The latter cells were significantly less susceptible to various lethal stimuli including anti-Fas, H(2)O(2), etoposide, and serum withdrawal than the former. These stimuli were found to kill the SNU-16 cells by activating stress-activated protein kinase (SAPK)/c-Jun NH(2)-terminal kinase (JNK), whereas SAPK/JNK activation was not efficiently induced in the SNU-620 cells. Western blot analysis revealed that Bcl-w, but not the other tested members of the Bcl-2 family, was expressed in the SNU-620 cells to levels higher than that observed in SNU-16 cells. An elevation of the Bcl-w levels in the SNU-16 cells by its stable transfection attenuated both the SAPK/JNK activation and the cell death induced by all of the tested stimuli. These results suggest that the susceptibility of gastric cancer cells to death stimuli is determined, at least in part, by the levels of Bcl-w that suppress the cell death by blocking SAPK/JNK activation. To examine whether Bcl-w was expressed in patients, tumor specimens were obtained from 50 consecutive advanced gastric adenocarcinoma cases. An immunohistochemical analysis showed that Bcl-w was expressed in cancer cells but not in the neighboring normal mucosa of the 23 cases (46%). Interestingly, Bcl-w expression was associated significantly with certain histopathological characteristics of the cancer, notably with the infiltrative morphotypes (P < 0.001). Therefore, Bcl-w appears to be important for gastric cancer cell survival, particularly in infiltrative tumors.
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PMID:Bcl-w is expressed in a majority of infiltrative gastric adenocarcinomas and suppresses the cancer cell death by blocking stress-activated protein kinase/c-Jun NH2-terminal kinase activation. 1261 27

Overexpression of urokinase plasminogen activator (uPA) is known to correlate closely with tumor cell invasion and metastasis. In gastric cancer, however, the mechanism for induction of uPA remains to be elucidated. In this study, we investigated the intracellular signaling for uPA expression in human gastric carcinoma cells (AGS, SNU-1, SNU-5, and SNU-638). SNU-638 cells which expressed a high level of uPA was found to be highly invasive on a matrigel, while AGS, SNU-1, and SNU-5 cells with low levels of uPA expression were only slightly invasive. SNU-638 cells showed a much higher P38 MAPK activity than the 3 other cell lines. However, there was no significant difference in the activities of P44/42 MAPK (Erk-1/2), JNK and Akt among the above cell lines. Treatment of SNU-638 cells with SB203580, a specific P38 MAPK inhibitor, reduced both the promoter activity and mRNA expression of uPA. Expression of a vector encoding a mutated-type P38alpha MAPK resulted in decrease in the uPA promoter activity in SNU-638 cells. These results suggest that P38 MAPK signaling pathway is important for uPA expression in gastric SNU-638 cells by enhancing the promoter activity of uPA.
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PMID:P38 MAPK pathway is involved in the urokinase plasminogen activator expression in human gastric SNU-638 cells. 1288 25


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