UMLS:C0684249 - FACTA Search

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Query: UMLS:C0684249 (lung carcinoma)
23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Approximately 15-25% of all primary cancers of the lung are classified histologically as small cell lung carcinoma (SCLC), a subtype characterized by rapid growth and a poor prognosis. Neuropeptide hormones like bombesin/gastrin-releasing peptide, bradykinin or galanin are the principal mitogenic stimuli of this tumour entity. The mitogenic signal is transmitted into the cell via heptahelical neuropeptide hormone receptors, which couple to the heterotrimeric G proteins of the Gq/11 familiy. Subsequent activation of phospholipase Cbeta (PLCbeta) entails the activation of protein kinase C and the elevation of the intracellular calcium concentration. There is mounting evidence to support the notion that calcium mobilization is the key event that initiates different mitogen-activated protein kinase cascades. Neuropeptide-dependent proliferation of SCLC cells relies on parallel activation of the Gq/11/PLCbeta/Ras/extracellular signal-regulated kinase and the c-jun N-terminal kinase pathways, while selective engagement of either signalling cascade alone results in growth arrest and differentiation or apoptotic cell death. Basic experimental research has the potential to identify and validate novel therapeutic targets located at critical points of convergence of different mitogenic signal transduction pathways. In the case of SCLC, targeting the distinct components of the Ca2+ influx pathway as well as critical Ca2+-dependent cellular effectors may be rewarding in this regard.
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PMID:Calcium-dependent growth regulation of small cell lung cancer cells by neuropeptides. 1715 54

We have previously demonstrated that fibronectin (Fn) stimulates the proliferation of non-small cell lung carcinoma (NSCLC) cell growth through the induction of cyclooxygenase-2 (COX-2) and prostaglandin E2 secretion. Here, we demonstrate that NSCLC cells express mRNA and protein for the prostaglandin E2 receptor EP4 and that Fn enhances its stimulatory effect by inducing the expression of EP4, but not of EP1, EP2, and EP3 receptor subtypes. The effect of Fn on EP4 was inhibited by an antibody against alpha5beta1 integrin and by inhibitors of phosphoinositide 3-kinase (wortmannin) and extracellular signal-regulated kinase (PD98095), but not by inhibitors of protein kinase C (calphostin C), of protein kinase A (H-89), or of mammalian target of rapamycin (rapamycin). A COX-2 small interfering RNA was also inhibitory. Fn significantly increased AP-2 binding activity in the promoter of the EP4 gene, and AP-2 antisense oligonucleotides blocked Fn-induced EP4 expression. Using full-length and mutated EP4 promoter constructs, we found that Fn stimulation of EP4 gene expression was inhibited when one AP-2 site (-1000 bp) was mutated. Fn induced nuclear AP-2alpha protein expression through multiple signaling pathways. Our results indicate that Fn-induced NSCLC cell proliferation is mediated through EP4. Furthermore, they show that Fn induces EP4 expression through the activation of alpha5beta1-dependent signals that include induction of extracellular signal-regulated kinase and phosphoinositide 3-kinase pathways as well as expression of COX-2. These events lead to activation of the transcription factor AP-2alpha, which interacts with specific regions in the EP4 gene promoter, leading to transcription of the EP4 gene.
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PMID:Extracellular matrix fibronectin increases prostaglandin E2 receptor subtype EP4 in lung carcinoma cells through multiple signaling pathways: the role of AP-2. 2187 99

Luteolin was isolated from Scutellaria barbata D. Don (S. barbata). In the present study, we examined the underlying molecular mechanism of luteolin and its effect on in vivo tumor growth of Lewis lung carcinoma (LLC) cells. Luteolin exhibited antiproliferative activity against LLC cells with IC50 of 12 microM. Luteolin effectively increased Annexin-V-positive cells as well as sub G1 DNA portion as seen on flow cytometric analysis. Western blotting has revealed that luteolin effectively activates caspase 9 and 3, cleaves poly (ADP-ribose) polymerase (PARP), and increases the ratio of Bax/Bcl-2. Furthermore, mitochondrial membrane potential was reduced by luteolin as seen on fluorescence microscopy. Luteolin downregulated the expression of extracellular signal-regulated kinase (ERK) and Akt in a concentration-dependent manner. In addition, luteolin significantly inhibited the growth of LLC cells implanted on the flank of mice to 40% and 60% of untreated control group values at 2 mg/kg and 10 mg/kg, respectively. Similarly, luteolin significantly reduced the expression of proliferating cell nuclear antigen (PCNA) as well as increased the expression of terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) in tumor section of LLC-bearing mice as determined by immunohistochemistry. Taken together, these results suggest that luteolin exerts antitumor activity by caspase activation and ERK/Akt inhibition.
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PMID:Caspase activation and extracellular signal-regulated kinase/Akt inhibition were involved in luteolin-induced apoptosis in Lewis lung carcinoma cells. 1741 Jun 45

Luteolin was isolated from Scutellaria barbata D. Don (S. barbata). In the present study, we examined the underlying molecular mechanism of luteolin and its effect on in vivo tumor growth of Lewis lung carcinoma (LLC) cells. Luteolin exhibited antiproliferative activity against LLC cells with IC50 of 12 microM. Luteolin effectively increased Annexin-V-positive cells as well as sub G1 DNA portion as seen on flow cytometric analysis. Western blotting has revealed that luteolin effectively activates caspase 9 and 3, cleaves poly (ADP-ribose) polymerase (PARP), and increases the ratio of Bax/Bcl-2. Furthermore, mitochondrial membrane potential was reduced by luteolin as seen on fluorescence microscopy. Luteolin downregulated the expression of extracellular signal-regulated kinase (ERK) and Akt in a concentration-dependent manner. In addition, luteolin significantly inhibited the growth of LLC cells implanted on the flank of mice to 40% and 60% of untreated control group values at 2 mg/kg and 10 mg/kg, respectively. Similarly, luteolin significantly reduced the expression of proliferating cell nuclear antigen (PCNA) as well as increased the expression of terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) in tumor section of LLC-bearing mice as determined by immunohistochemistry. Taken together, these results suggest that luteolin exerts antitumor activity by caspase activation and ERK/Akt inhibition.
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PMID:Caspase activation and extracellular signal-regulated kinase/Akt inhibition were involved in luteolin-induced apoptosis in Lewis lung carcinoma cells. 1738 57

The mechanisms by which tobacco promotes lung cancer remain incompletely understood. Herein, we report that nicotine, a major component of tobacco, promotes the proliferation of cultured non-small cell lung carcinoma (NSCLC) cells; this effect was most noticeable at 5 days. However, nicotine had no effect on apoptosis of NSCLC cells. In experiments designed to unveil the mechanisms for this effect, we found that nicotine also stimulated mRNA and protein expression of fibronectin. Fibronectin is a matrix glycoprotein that regulates important cellular processes (e.g., adhesion, proliferation, and differentiation) and is highly expressed in tobacco-related lung disorders. Of note, reagents against the integrin alpha5beta1 (antibodies, RGD peptides, alpha5 shRNA) blocked the mitogenic effects of nicotine. Thus, nicotine stimulated NSCLC cell proliferation indirectly via fibronectin induction. We then focused on the mechanisms responsible for nicotine-induced fibronectin expression in NSCLC cells and found that nicotine stimulated the surface expression of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR), and that alpha-bungarotoxin, an inhibitor of alpha7 nAChR, abolished the nicotine-induced fibronectin response. The fibronectin-inducing effects of nicotine were associated with activation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR) signaling pathways, and were abrogated by inhibitors of ERK (PD98059), PI3-K (LY294002), and mTOR (rapamycin), but not by inhibitors of protein kinase (PK)C (calphostin C) and PKA (H89). These observations suggest that nicotine stimulates NSCLC proliferation through induction of fibronectin, and that these events are mediated through nAChR-mediated signals that include ERK and PI3-K/mTOR pathways. This work highlights the role of fibronectin and alpha5beta1 integrins as potential targets for anti-lung cancer therapies.
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PMID:Nicotine stimulates human lung cancer cell growth by inducing fibronectin expression. 1760 Mar 15

Regular consumption of fruits and vegetables is strongly associated with reduced risk of developing chronic diseases. It is estimated that one third of all cancer deaths in the USA could be avoided through appropriate dietary modification. Several studies have indicated that fruits, vegetables and whole grains contain significant amounts of bioactive phytochemicals that have antiproliferative and antineoplastic properties. The bioactive phytochemicals may help protect cellular systems from oxidative damage as well as reduce the risk of chronic diseases. Quercetin and other related flavonoids have been shown to inhibit carcinogen-induced tumors in rodents. In humans, the total average intake of quercetin and kaempferol is estimated at 20 mg/day and consumption of quercetin from onions and apples was inversely correlated with lung cancer risk. In this study, we report that quercetin-inhibited A549 lung carcinoma cell proliferation was associated with activation of the extracellular signal-regulated kinase (ERK). Inhibition of MEK1/2 but not PI3 kinase, p38 kinase or JNK abolished quercetin-induced apoptosis suggesting MEK-ERK activation was required to trigger apoptosis.
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PMID:Dietary quercetin inhibits proliferation of lung carcinoma cells. 1768 11

Farnesol (FOH) and other isoprenoid alcohols induce apoptosis in various carcinoma cells and inhibit tumorigenesis in several in vivo models. However, the mechanisms by which they mediate their effects are not yet fully understood. In this study, we show that FOH is an effective inducer of apoptosis in several lung carcinoma cells, including H460. This induction is associated with activation of several caspases and cleavage of poly(ADP-ribose) polymerase (PARP). To obtain insight into the mechanism involved in FOH-induced apoptosis, we compared the gene expression profiles of FOH-treated and control H460 cells by microarray analysis. This analysis revealed that many genes implicated in endoplasmic reticulum (ER) stress signaling, including ATF3, DDIT3, HERPUD1, HSPA5, XBP1, PDIA4, and PHLDA1, were highly up-regulated within 4 h of FOH treatment, suggesting that FOH-induced apoptosis involves an ER stress response. This was supported by observations showing that treatment with FOH induces splicing of XBP1 mRNA and phosphorylation of eIF2alpha. FOH induces activation of several mitogen-activated protein kinase (MAPK) pathways, including p38, MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK, and c-jun NH2-terminal kinase (JNK). Inhibition of MEK1/2 by U0126 inhibited the induction of ER stress response genes. In addition, knockdown of the MEK1/2 and JNK1/2 expression by short interfering RNA (siRNA) effectively inhibited the cleavage of caspase-3 and PARP and apoptosis induced by FOH. However, only MEK1/2 siRNAs inhibited the induction of ER stress-related genes, XBP1 mRNA splicing, and eIF2alpha phosphorylation. Our results show that FOH-induced apoptosis is coupled to ER stress and that activation of MEK1/2 is an early upstream event in the FOH-induced ER stress signaling cascade.
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PMID:Farnesol-induced apoptosis in human lung carcinoma cells is coupled to the endoplasmic reticulum stress response. 1769

The novel lignan isochaihulactone inhibits cell proliferation and is an effective inducer of apoptosis in a variety of carcinoma cell lines. To determine the mechanisms underlying these effects, we examined isochaihulactone-induced changes in gene expression using oligodeoxynucleotide-based microarray screening of a human lung carcinoma cell line, A549. Isochaihulactone-inducible genes included the early growth response gene-1 (EGR-1) and nonsteroidal anti-inflammatory drug-activated gene (NAG-1). Isochaihulactone increased EGR-1 and then NAG-1 mRNA and protein expression. Pure isochaihulactone induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Isochaihulactone-induced increases in EGR-1 and NAG-1 expression were reduced by the mitogen-activated protein kinase kinase 1/2 inhibitor 2'-amino-3'-methoxyflavone (PD98059), and this effect was not blocked by the phosphatidylinositol 3-kinase/protein kinase B pathway inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002). Inhibition of isochaihulactone-induced NAG-1 expression by EGR-1 small interfering RNA blocked isochaihulactone-induced apoptosis in A549 cells, suggesting that induction of EGR-1 expression decreases survival of A549 cells. RNA interference using double-stranded RNA specific for NAG-1 also inhibited isochaihulactone-induced apoptosis, and cells transfected to increased NAG-1 expression had a greater apoptotic response to isochaihulactone and reduced colony formation efficiency. In addition, treatment of nude mice with isochaihulactone increased the in vivo NAG-1 expression as examined by immunohistochemistry from tumor biopsy. Isochaihulactone treatment increased the luciferase activity of NAG-1 in A549 cells transfected with the NAG-1 promoter construct. This induction increased expression of NAG-1 that was p53-independent and Sp1-dependent. Our findings suggest that NAG-1 expression is up-regulated by isochaihulactone through an ERK-dependent pathway involving the activation of EGR-1.
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PMID:Activation of nonsteroidal anti-inflammatory drug-activated gene-1 via extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase revealed a isochaihulactone-triggered apoptotic pathway in human lung cancer A549 cells. 1771 78

Signal transducer and activators of transcription 3 (STAT3) is an important transcription factor that is essential for lung cancer cell survival. STAT3 is activated by diverse upstream receptor and nonreceptor tyrosine kinases, and blockade of STAT3 results in tumor growth inhibition. Therefore, a search for STAT3 inhibitors is under way. We demonstrate that SCH66336, at 4 mumol/l, completely blocks STAT3 phosphorlyation in a variety of nonsmall cell lung carcinoma (NSCLC) cell lines, whereas the effect on AKT and extracellular signal-regulated kinase activation is variable. Furthermore, SCH66336 has antiproliferative effects on NSCLC cells. When NSCLC cells are exposed sequentially to SCH66336 and a small molecule dual tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2, synergistic activity is observed with an increase in the fraction of cells undergoing apoptosis. Concurrent exposure to both agents is, however, associated with antagonism and decreased apoptosis. We conclude that blockade of STAT3 phosphorylation might be one of the mechanisms by which SCH66336 exerts its antitumor activity, and that this can be synergistic in vitro when administered sequentially with epidermal growth factor receptor inhibitors.
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PMID:SCH66336, inhibitor of protein farnesylation, blocks signal transducer and activators of transcription 3 signaling in lung cancer and interacts with a small molecule inhibitor of epidermal growth factor receptor/human epidermal growth factor receptor 2. 1804 25

Most cancers are dependent on the growth of tumor blood vessels and inhibition of tumor angiogenesis may thus provide an efficient strategy to retard or block tumor growth. Recently, tumor vascular targeting has expanded to include not only endothelial cells (ECs) but also smooth muscle cells (SMCs), which contribute to a mature and functional vasculature. We have reported previously that delphinidin, a major biologically active constituent of berries, inhibits the vascular endothelial growth factor-induced phosphorylation of vascular endothelial growth factor receptor-2 and blocks angiogenesis in vitro and in vivo. In the present study, we show that delphinidin also inhibits activation of the platelet-derived growth factor (PDGF)-BB receptor-beta [platelet-derived growth factor receptor-beta (PDGFR-beta)] in SMC and that this inhibition may contribute to its antitumor effect. The inhibitory effect of delphinidin on PDGFR-beta was very rapid and led to the inhibition of PDGF-BB-induced activation of extracellular signal-regulated kinase (ERK)-1/2 signaling and of the chemotactic motility of SMC, as well as the differentiation and stabilization of EC and SMC into capillary-like tubular structures in a three-dimensional coculture system. Using an anthocyan-rich extract of berries, we show that berry extracts were able to suppress the synergistic induction of vessel formation by basic fibroblast growth factor-2 and PDGF-BB in the mouse Matrigel plug assay. Oral administration of the berry extract also significantly retarded tumor growth in a lung carcinoma xenograft model. Taken together, these results provide new insight into the molecular mechanisms underlying the antiangiogenic activity of delphinidin that will be helpful for the development of dietary-based chemopreventive strategies.
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PMID:Delphinidin, a dietary anthocyanidin, inhibits platelet-derived growth factor ligand/receptor (PDGF/PDGFR) signaling. 1833 83

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