Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas/FasL system has been extensively investigated with respect to its capacity to induce cellular apoptosis. However, accumulated evidences show that Fas signaling also exhibits nonapoptotic functions, such as induction of cell proliferation and differentiation. Lung cancer is one of cancer's refractory to the immunotherapy, however, the underlying mechanisms remain to be fully understood. In this study, we show that Fas overexpression does not affect in vitro growth of 3LL cells, but promotes lung cancer growth in vivo. However, such tumor-promoting effect is not observed in FasL-deficient (gld) mice, and also not observed in the immune competent mice once inoculation with domain-negative Fas-overexpressing 3LL cells, suggesting the critical role of Fas signal in the promotion of lung cancer growth in vivo. More accumulation of myeloid-derived suppressor cells (MDSC) and Foxp3(+) regulatory T cells is found in tumors formed by inoculation with Fas-overexpressing 3LL cells, but not domain-negative Fas-overexpressing 3LL cells. Accordingly, Fas-ligated 3LL lung cancer cells can chemoattract more MDSC but not regulatory T cells in vitro. Furthermore, Fas ligation induces 3LL lung cancer cells to produce proinflammatory factor PGE(2) by activating p38 pathway, and in turn, 3LL cells-derived PGE(2) contribute to the Fas ligation-induced MDSC chemoattraction. Furthermore, in vivo administration of cyclooxygenase-2 inhibitor can significantly reduce MDSC accumulation in the Fas-overexpressing tumor. Therefore, our results demonstrate that Fas signal can promote lung cancer growth by recruiting MDSC via cancer cell-derived PGE(2), thus providing new mechanistic explanation for the role of inflammation in cancer progression and immune escape.
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PMID:Fas signal promotes lung cancer growth by recruiting myeloid-derived suppressor cells via cancer cell-derived PGE2. 2063 52

The expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) inhibits gastrointestinal tumorigenesis in NAG-1 transgenic mice (C57/BL6 background). In the present study, we investigated whether the NAG-1 protein would alter urethane-induced pulmonary lesions in NAG-1 transgenic mice on an FVB background (NAG-1(Tg+/FVB)). NAG-1(Tg+/FVB) mice had both decreased number and size of urethane-induced tumors, compared with control littermates (NAG-1(Tg+/FVB) = 16 +/- 4 per mouse versus control = 20 +/- 7 per mouse, P < 0.05). Urethane-induced pulmonary adenomas and adenocarcinomas were observed in control mice; however, only pulmonary adenomas were observed in NAG-1(Tg+/FVB) mice. Urethane-induced tumors from control littermates and NAG-1(Tg+/FVB) mice highly expressed proteins in the arachidonic acid pathway (cyclooxygenases 1/2, prostaglandin E synthase, and prostaglandin E(2) receptor) and highly activated several kinases (phospho-Raf-1 and phosphorylated extracellular signal-regulated kinase 1/2). However, only urethane-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation was decreased in NAG-1(Tg+/FVB) mice. Furthermore, significantly increased apoptosis in tumors of NAG-1(Tg+/FVB) mice compared with control mice was observed as assessed by caspase-3/7 activity. In addition, fewer inflammatory cells were observed in the lung tissue isolated from urethane-treated NAG-1(Tg+/FVB) mice compared with control mice. These results paralleled in vitro assays using human A549 pulmonary carcinoma cells. Less phosphorylated p38 MAPK was observed in cells overexpressing NAG-1 compared with control cells. Overall, our study revealed for the first time that the NAG-1 protein inhibits urethane-induced tumor formation, probably mediated by the p38 MAPK pathway, and is a possible new target for lung cancer chemoprevention.
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PMID:Nonsteroidal anti-inflammatory drug-activated gene-1 expression inhibits urethane-induced pulmonary tumorigenesis in transgenic mice. 1940 23

Lung cancer continues to be the leading cause of cancer deaths throughout the world and conventional therapy remains largely unsuccessful. Although, chemoprevention is a plausible alternative approach to curb the lung cancer epidemic, clinically there are no effective chemopreventive agents. Thus, development of novel compounds that can target cellular and molecular pathways involved in the multistep carcinogenesis process is urgently needed. Previous studies have suggested that substitution of sulfur by selenium in established cancer chemopreventive agents may result in more effective analogs. Thus in the present study we selected the chemopreventive agent S,S'-(1,4-phenylenebis[1,2-ethanediyl])bisisothiourea (PBIT), also known to inhibit inducible nitric oxide synthase (iNOS), synthesized its selenium analog (Se-PBIT) and compared both compounds in preclinical model systems using non-small cell lung cancer (NSCLC) cell lines (NCI-H460 and A549); NSCLC is the most common histologic type of all lung cancer cases. Se-PBIT was found to be superior to PBIT as an inducer of apoptosis and inhibitor of cell growth. Se-PBIT arrested cell cycles at G1 and G2-M stage in both A549 and H460 cell lines. Although both compounds are weakly but equally effective inhibitors of iNOS protein expression and activity, only Se-PBIT significantly enhanced the levels of p53, p38, p27 and p21 protein expression, reduced levels of phospholipase A2 (PLA2) but had no effect on cyclooxygenase-2 (COX-2) protein levels; such molecular targets are involved in cell growth inhibition, induction of apoptosis and cell cycle regulation. The results indicate that Se-PBIT altered molecular targets that are involved in the development of human lung cancer. Although, the mechanisms that can fully account for these effects remain to be determined, the results are encouraging to further evaluate the chemopreventive efficacy of Se-PBIT against the development of NSCLC in a well-defined animal model.
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PMID:The selenium analog of the chemopreventive compound S,S'-(1,4-phenylenebis[1,2-ethanediyl])bisisothiourea is a remarkable inducer of apoptosis and inhibitor of cell growth in human non-small cell lung cancer. 1949 13

Matrilysin-1 (also called matrix metalloproteinase-7) is expressed in injured lung and in cancer but not in normal epithelia. Bronchiolization of the alveoli (BOA), a potential precursor of lung cancer, is a histologically distinct type of metaplasia that is composed of cells resembling airway epithelium in the alveolar compartment. We demonstrate that there is increased expression of matrilysin-1 in human lesions and BOA in the CC10-human achaete-scute homolog-1 transgenic mouse model. Forced expression of the matrilysin-1 gene in immortalized human normal airway epithelial BEAS-2B and HPLD1 cells, which do not normally express matrilysin-1, promoted cellular migration, suggesting a functional link for BOA formation via bronchiolar cell migration. In addition, matrilysin-1 stimulated proliferation and inhibited Fas-induced apoptosis, while a knockdown by RNA interference decreased cell growth, migration, and increased sensitivity to apoptosis. Western blotting demonstrated increased levels of phospho-p38 and phospho-Erk1/2 kinases after matrilysin-1 expression. Gene expression analysis uncovered several genes that were related to cell growth, migration/movement, and death, which could potentially facilitate bronchiolization. In vivo, the formation of BOA lesions was reduced when CC10-human achaete-scute homolog-1 mice were crossed with matrilysin-1 null mice and was correlated with reduced matrilysin-1 expression in BOA. We conclude that matrilysin-1 may play an important role in the bronchiolization of alveoli by promoting proliferation, migration, and attenuation of apoptosis involving multiple genes in the MAP kinase pathway.
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PMID:Matrilysin-1 mediates bronchiolization of alveoli, a potential premalignant change in lung cancer. 1960 71

Humic acid, a group of polymer, resulting from the decomposition of organic matter has been implicated as a possible etiological factor for Black foot disease and cancer. However, the role of humic acid in carcinogenesis is not well clarified. In this study, we evaluated the enhancement effect of humic acid on the progression of A549 human lung cancer cells. Our findings showed that humic acid increased the migration, adhesion and invasion of A549 cells significantly after treatment at the concentration of 50 and 100 microg/ml for 24 and 48 h as compared with the untreated group. Results of zymography assay indicated that humic acid enhanced the activity of matrix metalloproteinase 9 (MMP-9). By western blotting analysis, humic acid increased the expression of phosphorylated focal adhesion kinase (FAK) and integrin alpha2 that may mediate cell motility and adhesion. Since the activation of signal pathways such as phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinases (MAPKs) may play a role in the cell invasion, we detected the expression of phosphorylated Akt and phosphorylated MAPKs including extracellular signal-regulated kinase (ERK), Jun N-terminus kinase (JNK), and p38. The result indicated that all kinases stated above were activated by humic acid in A549 cells. However, by adding an inhibitor respectively in the invasion assay, only Akt, ERK, and JNK pathways were found to be involved in the enhancing the invasion of A549 cells by humic acid. In addition, results of electrophoretic mobility shift assay (EMSA) demonstrated that humic acid increased nuclear extract binding to the DNA probe of activator protein 1 (AP-1) and nuclear factor kappaB (NFkappaB) respectively, implying that humic acid enhanced the progression of A549 lung cancer cells through activating multiple signaling pathways including ERK, JNK, and PI3K/Akt and increasing the transcription activation of AP-1 and NFkappaB.
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PMID:In vitro enhancement effect of humic acid on the progression of lung cancer cells. 1968 14

This study investigates the anticancer effect of dehydrocostuslactone (DHE), a medicinal plant-derived sesquiterpene lactone, on human non-small cell lung cancer cell lines, A549, NCI-H460 and NCI-H520. Our results show that DHE inhibits the proliferation of A549, NCI-H460 and NCI-H520 cells. DHE-induced apoptosis in both A549 and NCI-H460 cells. DHE triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol-calcium levels, PKR-like ER kinase (PERK) phosphorylation, inositol requiring protein 1 (IRE1) and CHOP/GADD153 upregulation, X-box transcription factor-1 (XBP-1) mRNA splicing, and caspase-4 activation. The release of calcium triggered the production of ROS, which further enhances calcium overloading and subsequently activates p38, JNK and ERK1/2. Both IRE1 miRNA transfection and BAPTA-AM pretreatment inhibit DHE-mediated apoptosis, supporting the hypothesis that DHE induces cell death through ER stress. Importantly, a novel anticancer agent for the treatment of non-small cell lung cancer, and is supported by animal studies which have shown a dramatic 50% reduction in tumor size after 28 days of treatment. This study demonstrates that DHE may be a novel anticancer agent for the treatment of non-small cell lung cancer.
Lung Cancer 2010 Jun
PMID:Oxidative and endoplasmic reticulum stress signaling are involved in dehydrocostuslactone-mediated apoptosis in human non-small cell lung cancer cells. 1970 Feb 17

Antimycin A (AMA) inhibits succinate oxidase, NADH oxidase, and mitochondrial electron transport chain between cytochrome b and c. We recently demonstrated that AMA inhibited the growth of Calu-6 lung cancer cells through apoptosis. Here, we investigated the effects of AMA and/or MAPK inhibitors on Calu-6 lung cancer cells in relation to cell growth, cell death, reactive oxygen species (ROS), and GSH levels. Treatment with AMA inhibited the growth of Calu-6 cells at 72 h. AMA-induced apoptosis was accompanied by the loss of mitochondrial membrane potential (MMP; Delta Psi m). While ROS were decreased in AMA-treated Calu-6 cells, O2.- among ROS was increased. AMA also induced GSH depletion in Calu-6 cells. Treatment with MEK inhibitor intensified cell death, MMP (Delta Psi m) loss, and GSH depletion in AMA-treated Calu-6 cells. JNK inhibitor also increased cell death, MMP (Delta Psi m) loss, and ROS levels in these cells. Treatment with p38 inhibitor magnified cell growth inhibition by AMA and increased cell death, MMP (Delta Psi m) loss, ROS level, and GSH depletion in AMA-treated cells. Conclusively, all the MAPK inhibitors slightly intensified cell death in AMA-treated Calu-6 cells. The changes of ROS and GSH by AMA and/or MAPK inhibitors were in part involved in cell growth and death in Calu-6 cells.
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PMID:The effects of MAPK inhibitors on antimycin A-treated Calu-6 lung cancer cells in relation to cell growth, reactive oxygen species, and glutathione. 1971 50

Epithelial-mesenchymal transition (EMT) has emerged as a critical event in the pathogenesis of organ fibrosis and cancer and is typically induced by the multifunctional cytokine transforming growth factor (TGF)-beta1. The present study was undertaken to evaluate the potential role of phosphodiesterases (PDEs) in TGF-beta1-induced EMT in the human alveolar epithelial type II cell line A549. Stimulation of A549 with TGF-beta1 induced EMT by morphological alterations and by expression changes of the epithelial phenotype markers E-cadherin, cytokeratin-18, zona occludens-1, and the mesenchymal phenotype markers, collagen I, fibronectin, and alpha-smooth muscle actin. Interestingly, TGF-beta1 stimulation caused twofold increase in total cAMP-PDE activity, contributed mostly by PDE4. Furthermore, mRNA and protein expression demonstrated up-regulation of PDE4A and PDE4D isoforms in TGF-beta1-stimulated cells. Most importantly, treatment of TGF-beta1 stimulated epithelial cells with the PDE4-selective inhibitor rolipram or PDE4 small interfering RNA potently inhibited EMT changes in a Smad-independent manner by decreasing reactive oxygen species, p38, and extracellular signal-regulated kinase phosphorylation. In contrast, the ectopic overexpression of PDE4A and/or PDE4D resulted in a significant loss of epithelial marker E-cadherin but did not result in changes of mesenchymal markers. In addition, Rho kinase signaling activated by TGF-beta1 during EMT demonstrated to be a positive regulator of PDE4. Collectively, the findings presented herein suggest that TGF-beta1 mediated up-regulation of PDE4 promotes EMT in alveolar epithelial cells. Thus, targeting PDE4 isoforms may be a novel approach to attenuate EMT-associated lung diseases such as pulmonary fibrosis and lung cancer.
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PMID:Expression and activity of phosphodiesterase isoforms during epithelial mesenchymal transition: the role of phosphodiesterase 4. 1975 79

Arsenic trioxide (ATO) can regulate many biological functions such as apoptosis and differentiation. We recently demonstrated that ATO-induced apoptosis in Calu-6 lung cancer cells is correlated with glutathione (GSH) content. Here, the effects of ATO and/or mitogen-activated protein kinase (MAPK) inhibitors on Calu-6 cells were investigated in relation to cell growth, cell death, reactive oxygen species (ROS) and GSH levels. Treatment with ATO inhibited the growth of the Calu-6 cells at 72 hours. ATO induced apoptosis, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). While general nonspecific ROS decreased in the ATO-treated Calu-6 cells, the intracellular superoxide anion (O(2)(-)) level including mitochondrial O(2)(-) increased. ATO also induced GSH depletion in the Calu-6 cells. The treatment with MAP kinase kinase (MEK), c-Jun N-terminal kinase (JNK) and p38 inhibitors intensified the cell growth inhibition, cell death, MMP (DeltaPsi(m)) loss, and GSH depletion in the ATO-treated Calu-6 cells. In addition, the JNK and p38 inhibitors significantly increased the ROS levels including O(2)(-) in the ATO-treated Calu-6 cells. In conclusion, all the MAPK inhibitors slightly intensify cell death in the ATO-treated Calu-6 cells and the changes of ROS and GSH brought about by ATO and/or MAPK inhibitor treatment partially influence cell growth and death in Calu-6 cells.
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PMID:The effect of MAPK inhibitors on arsenic trioxide-treated Calu-6 lung cells in relation to cell death, ROS and GSH levels. 1984 17

The peroxiredoxin family of peroxidase has six mammalian members (Prx 1-6). Considering their frequent up-regulation in cancer cells, Prxs may contribute to cancer cells' survival in face of oxidative stress. Here, we show that Prx 6 promotes the invasiveness of lung cancer cells, accompanied by an increase in the activity of phosphoinositide 3-kinase (PI3K), the phosphorylation of p38 kinase and Akt, and the protein levels of uPA. Functional studies reveal that these components support Prx 6-induced invasion in the sequence p38 kinase/PI3K, Akt, and uPA. The findings provide a new understanding of the action of Prx 6 in cancer.
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PMID:Peroxiredoxin 6 promotes lung cancer cell invasion by inducing urokinase-type plasminogen activator via p38 kinase, phosphoinositide 3-kinase, and Akt. 1993 38


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