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

Kiss-1 has been identified as a putative metastasis suppressor gene in various human malignancies. However, there is little information about its possible role in gastric carcinoma. In this study, we determined whether the Kiss-1 gene negatively regulates MMP-9 expression. cDNA microarray technology was used to identify the genes associated with metastasis by hepatocyte growth factor (HGF) in the gastric cancer cell lines, NUGC-3 and MKN-28. The levels of Kiss-1 RNA and protein were confirmed to be upregulated in HGF-treated gastric cancer cells. HGF induced Kiss-1 and MMP-9 production in a dose-dependent manner. In order to investigate roles of HGF signaling in tumor progression and metastasis, we measured effects of a specific MEK1 inhibitor (PD 098059) and a p38 kinase inhibitor (SB 203580) on HGF-mediated cell proliferation and MMP-9. Pretreatment with PD 098059 reduced MMP-9 and HGF-mediated cell proliferation, but increased Kiss-I expression. In contrast, SB 203580 pretreatment enhanced MMP-9 and cell prolifera-tion, but decreased Kiss-1 expression. Cotreatment of PD098059 and SB203580 increased the p38 phosphorylation stimulated by HGF. These results suggest that the HGF-mediated Kiss-1 overexpression is regulated mainly by the p38 activation and, furthermore, the activation of ERK might affect HGF-mediated Kiss-1 expression indirectly by the regulation of p38 kinase. Consistent with this result, p38 phosphorylation was strongly repressed by the knock-down of Kiss-1. Downregulation of Kiss-1 using Kiss-1 shRNA also increased in vitro cell invasion. In conclusion, Kiss-1 suppresses MMP-9 expression by activating the p38 MAP kinase signaling pathway.
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PMID:Kiss-1 suppresses MMP-9 expression by activating p38 MAP kinase in human stomach cancer. 2006

The ubiquitin-proteasome system and macroautophagy are two complementary pathways for protein degradation. Emerging evidence suggests that proteasome inhibition might be a promising approach for the treatment of cancer. In this study, we show that proteasome inhibitor MG-132 suppressed gastric cancer cell proliferation and induced macroautophagy. The induction of macroautophagy was evidenced by the formation of LC3(+) autophagosomes and the accumulation of acidic vesicular organelles and autolysosomes and was accompanied by the suppression of mammalian target of rapamycin complex 1 activity. Abolition of macroautophagy by knockdown of Class III phosphatidylinositol-3 kinase Vps34 or ATG5/7 sensitized gastric cancer cells to the antiproliferative effect of MG-132 by promoting G(2)/M cell cycle arrest. In addition, MG-132 increased ERK phosphorylation whose inhibition by MEK inhibitor significantly enhanced the antiproliferative effect of proteasome inhibition. To conclude, this study demonstrates that macroautophagy and ERK phosphorylation serve as protective mechanisms to counteract the antiproliferative effect of proteasome inhibition. This discovery may have implications for the application of proteasome-directed therapy for the treatment of cancer.
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PMID:Macroautophagy and ERK phosphorylation counteract the antiproliferative effect of proteasome inhibitor in gastric cancer cells. 2008 64

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been used to treat a variety of cancer cells. However, since some gastric cancer cells are resistant to TRAIL, we explored whether reovirus induces cytolysis in TRAIL-resistant gastric cancer cells. We found that TRAIL-resistant SNU-216 gastric cancer cells were susceptible to apoptosis by reovirus infection. Furthermore, co-treatment with reovirus and TRAIL accelerated apoptosis of SNU-216 cells by down-regulation of Akt activation as assessed by a very low activation of Akt in TRAIL-sensitive SNU-668 gastric cancer cells. Inhibition of Akt signaling with wortmannin or suppression of Akt expression with sh-Akt lentivirus promoted reovirus-mediated apoptosis of SNU-216 gastric cancer cells. Reovirus infection also down-regulates the activation of signaling molecules such as Ras and ERK involved in cell proliferation and survival but not the activation of p38 MAPK involved in cellular stress. In addition, the co-treatment with reovirus and TRAIL resulted in cleavage of caspase-8, caspase-9 and Bid, leading to a decrease in the mitochondrial membrane potential, indicating that reovirus may utilize the mitochondrial intrinsic apoptotic pathway in TRAIL-resistant SNU-216 gastric cancer cells. Accordingly, we first demonstrate that reovirus infection down-regulates Akt activation, leading to apoptosis of TRAIL-resistant gastric cancer cells.
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PMID:Reovirus infection induces apoptosis of TRAIL-resistant gastric cancer cells by down-regulation of Akt activation. 2019 49

Recently, we reported that reduction of intracellular Cl(-) concentration ([Cl(-)](i)) inhibited proliferation of MKN28 gastric cancer cells by diminishing the transition rate from G(1) to S cell-cycle phase through upregulation of p21, cyclin-dependent kinase inhibitor, in a p53-independent manner. However, it is still unknown how intracellular Cl(-) regulates p21 expression level. In this study, we demonstrate that mitogen-activated protein kinases (MAPKs) are involved in the p21 upregulation and cell-cycle arrest induced by reduction of [Cl(-)](i). Culture of MKN28 cells in a low Cl(-) medium significantly induced phosphorylation (activation) of MAPKs (ERK, p38, and JNK) and G(1)/S cell-cycle arrest. To clarify the involvement of MAPKs in p21 upregulation and cell growth inhibition in the low Cl(-) medium, we studied effects of specific MAPKs inhibitors on p21 upregulation and G(1)/S cell-cycle arrest in MKN28 cells. Treatment with an inhibitor of p38 or JNK significantly suppressed p21 upregulation caused by culture in a low Cl(-) medium and rescued MKN28 cells from the low Cl(-)-induced G(1) cell-cycle arrest, whereas treatment with an ERK inhibitor had no significant effect on p21 expression or the growth of MKN28 cells in the low Cl(-) medium. These results strongly suggest that the intracellular Cl(-) affects the cell proliferation via activation of p38 and/or JNK cascades through upregulation of the cyclin-dependent kinase inhibitor (p21) in a p53-independent manner in MKN28 cells.
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PMID:Intracellular chloride regulates cell proliferation through the activation of stress-activated protein kinases in MKN28 human gastric cancer cells. 2020 50

The Helicobacter pylori protein CagA may undergo tyrosine phosphorylation following its entry into human gastric epithelial cells with downstream effects on signal transduction. Disruption of the gp130 receptor that modulates the balance of the SHP2/ERK and JAK/STAT pathways enhanced peptic ulceration and gastric cancer in gp130 knock-out mice. In this study, we evaluated the effect of translocated CagA in relation to its tyrosine phosphorylation status on the gp130-mediated signal switch between the SHP2/ERK and JAK/STAT3 pathways. We showed that in the presence of CagA, SHP2 was recruited to gp130. Phosphorylated CagA showed enhanced SHP2 binding activity and ERK1/2 phosphorylation, whereas unphosphorylated CagA showed preferential STAT3 activation. These findings indicate that the phosphorylation status of CagA affects the signal switch between the SHP2/ERK and JAK/STAT3 pathways through gp130, providing a novel mechanism to explain H. pylori signaling.
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PMID:Helicobacter pylori CagA phosphorylation status determines the gp130-activated SHP2/ERK and JAK/STAT signal transduction pathways in gastric epithelial cells. 2034 91

KRAS is frequently mutated in nonsmall cell lung cancer (NSCLC), resulting in the activation of the MAPK/ERK kinase (MEK)/ERK pathway. High-throughput mutation profile has shown that lung cancer frequently harbors comutation of cancer-related genes. Therefore, given that cancer cells have multiple genetic alterations, combinatorial therapeutic strategy is demanded for effective cancer therapy. To address this, we first characterized MEK dependence in four NSCLC cells. Two cells (H358, A549) carried KRAS mutation only, and the other two (H23, H157) harbored comutation of KRAS/PTEN. H358 cells with KRAS mutation only were sensitive to MEK inhibition. However, the other KRAS mutant A549 cells were resistant to MEK inhibition. Previously, we have shown that dual inhibition of EGFR and MEK signaling shows a synergistic effect on KRAS mutant gastric cancer cells by suppressing compensatory activation of AKT. Here we also observed that this combination was effective in KRAS mutant A549 cells. However, the combination was ineffective in H23 and 157 cells with comutation of KRAS/PTEN. Compared to KRAS mutant/PTEN wild-type cells, signal transducer and activator of transcription 3 (STAT3) was significantly activated following MEK inhibition in KRAS/PTEN comutant cells. Combined STAT3 inhibition by a JAK2 inhibitor or gene knockdown with MEK inhibition blocked STAT3 activation, synergistically suppressed cell growth, and induced apoptosis in comutant cells. Taken together, our study provides molecular insights that help explain the heterogeneous response to MEK inhibition in KRAS mutant lung cancers, and presents a rationale for the clinical investigation of combination of MEK and EGFR inhibitor or MEK and JAK2 inhibitor depending on PTEN status.
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PMID:KRAS mutant lung cancer cells are differentially responsive to MEK inhibitor due to AKT or STAT3 activation: implication for combinatorial approach. 2035 31

Macrophages are essential components of innate immunity, and apoptosis of these cells impairs mucosal defense to microbes. Helicobacter pylori is a gastric pathogen that infects half of the world population and causes peptic ulcer disease and gastric cancer. The host inflammatory response fails to eradicate the organism. We have reported that H. pylori induces apoptosis of macrophages by generation of polyamines from ornithine decarboxylase (ODC), which is dependent on c-Myc as a transcriptional enhancer. We have now demonstrated that expression of c-Myc requires phosphorylation and nuclear translocation of ERK, which results in phosphorylation of c-Fos and formation of a specific activator protein (AP)-1 complex. Electromobility shift assay and immunoprecipitation revealed a previously unrecognized complex of phospho-c-Fos (pc-Fos) and c-Jun in the nucleus. Fluorescence resonance energy transfer demonstrated the interaction of pc-Fos and c-Jun. The capacity of this AP-1 complex to bind to putative AP-1 sequences was demonstrated by oligonucleotide pulldown and fluorescence polarization. Binding of the pc-Fos.c-Jun complex to the c-Myc promoter was demonstrated by chromatin immunoprecipitation. A dominant-negative c-Fos inhibited H. pylori-induced expression of c-Myc and ODC and apoptosis. H. pylori infection of mice induced a rapid infiltration of macrophages into the stomach. Concomitant apoptosis depleted these cells, and this was associated with formation of a pc-Fos.c-Jun complex. Treatment of mice with an inhibitor of ERK phosphorylation attenuated phosphorylation of c-Fos, expression of ODC, and apoptosis in gastric macrophages. A unique AP-1 complex in gastric macrophages contributes to the immune escape of H. pylori.
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PMID:Helicobacter pylori induces ERK-dependent formation of a phospho-c-Fos c-Jun activator protein-1 complex that causes apoptosis in macrophages. 2041 Mar 4

Hypoxia is recognized as an important factor contributing to cancer development and drug resistance. Cetuximab, a chimeric monoclonal antibody to EGFR, is known to inhibit HIF-1 alpha expression levels and to enhance the cytotoxicity of chemotherapeutic agents. We demonstrated that hypoxia induced drug resistance in gastric cancer cells. Cetuximab enhanced oxaliplatin-induced cytotoxicity and apoptosis in normoxia and caused a reversal of drug resistance in hypoxia. Normoxic and hypoxic gastric cancer cells were treated with cetuximab, oxaliplatin or the combination and assessed for cell growth, proliferation, and apoptosis. Combination treatment resulted in a marked inhibition of HIF-1 alpha expression levels in hypoxic cells and caused a significant reduction in the expression of activated phosphorylated AKT, ERK1/2, p-BAD and VEGF in both normoxia and hypoxia with greater levels of inhibition in hypoxia. In summary, cetuximab inhibits HIF-1 alpha expression via the MAPK/ERK and PI3K/AKT signaling pathways and functions to overcome drug resistance induced by hypoxia. Cetuximab-oxaliplatin combination therapy may therefore emerge as an attractive treatment strategy for advanced gastric cancer.
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PMID:Cetuximab enhances the effect of oxaliplatin on hypoxic gastric cancer cell lines. 2042 33

It has been reported that the 67-kDa laminin receptor (67LR) is implicated in cancer metastasis. We recently showed that 37LRP, the 67LR precursor, is a hypoxia-inducible factor 1 (HIF-1) target gene exposed to hypoxia in gastric cancer. Here, we investigated the role of 67LR in hypoxic metastasis and invasion in gastric cancer. Immunohistochemical analysis, western blotting, and RT-PCR assays revealed that 67LR was highly expressed in metastatic gastric cancers in vivo. Knockdown of the 67LR protein by RNA interference significantly decreased the adhesive, invasive, and in vivo metastatic abilities of the gastric cancer cell lines SGC7901 and MKN-45. Western blot analysis showed that 67LR increased the expression of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP)-9, and decreased tissue inhibitor of matrix metalloproteinase (TIMP)-1 protein. We further showed that hypoxia induced 67LR expression in a time-dependent manner and this induction was inhibited by HIF-1 small-interfering (si) RNA. Both ERK and JNK inhibitors significantly inhibited hypoxia-induced expression of 67LR and the subsequent expression of uPA and MMP 9. SiRNA against 67LR or antibody against MMP9 and uPA significantly inhibited hypoxia-induced in vitro invasive ability. Taken together, these results reveal that 67LR promotes the invasive and metastatic ability of the gastric cancer cells through increasing uPA and MMP 9 expression, with involvement of the ERK and JNK signal pathway in hypoxia-induced 67 LR expressions and subsequent uPA and MMP9 expression.
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PMID:Hypoxia promotes metastasis in human gastric cancer by up-regulating the 67-kDa laminin receptor. 2049 81

Evaluation of: Turner N, Pearson A, Sharpe R et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 70(5), 2085-2094 (2010). FGF receptor (FGFR) family members are aberrantly activated during carcinogenesis due to gene amplification, chromosomal translocation and missense mutation. FGFR1 is preferentially amplified in estrogen receptor-positive breast cancer, whereas FGFR2 is amplified in triple-negative breast cancer and diffuse-type gastric cancer. Gene amplification of FGFRs results in ligand-independent FGFR signaling to RAS-ERK, PI3K-AKT and JAK-STAT cascades due to the overexpression of wild-type or C-terminally deleted FGFRs. Cediranib, TKI258, Ki23057, MK-2461 and brivanib are broad-range tyrosine kinase inhibitors targeting FGFRs and other receptors. Clinical application of small-molecule FGFR inhibitors could improve the prognosis of FGFR-driven cancer patients. Diagnostic detection of tumors with FGFR genetic alterations in primary lesion, peritoneal effusion, pleural effusion and bone marrow is necessary to select patients for FGFR-targeted therapeutics.
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PMID:Genetic alterations of FGF receptors: an emerging field in clinical cancer diagnostics and therapeutics. 2017 96


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