Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein kinase C (PKC) family, which functions through serine/threonine kinase activity, is involved in signal transduction pathways necessary for cell proliferation and differentiation. Its critical role in processes relevant to neoplastic transformation and tumor invasion renders PKC a potentially suitable target for anticancer therapy. To explore whether antisense blocking of PKCalpha would inhibit the neoplastic properties in tumor cells, human lung carcinoma LTEPa-2 cells were transfected with a recombinant plasmid, pXJ41-CKPalpha, with PKCalpha cDNA inserted in the antisense orientation. In LT.AS4 cell clones stably expressing antisense PKCalpha mRNA, the amounts of PKCalpha protein and total PKC activity were decreased when compared to control cells. The expression of antisense PKCalpha markedly inhibited the cell proliferation rate, colony forming efficiency in soft agar, and tumorigenecity in nude mice. Furthermore, the mRNA levels of oncogenes (Ha-ras, c-jun, and c-fos) were seen to decrease to varying degrees. Reduced DNA binding activity of transcription factor AP-1 was also observed using gel shift analysis, suggesting that one major molecular mechanism by which PKCalpha can exert its effects on cell growth and transformation is through regulation of AP-1 transcription factor activity. Taken together, these data provide evidence for the ability of antisense PKCalpha expression to reverse the transformed phenotype of human lung carcinoma cells and support the development of PKCalpha inhibitors for the clinical treatment of cancers.
 ...
PMID:Antisense inhibition of protein kinase Calpha reverses the transformed phenotype in human lung carcinoma cells. 1038 39

Transcriptional activation of human manganese superoxide dismutase (MnSOD) mRNA induced by a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), was examined to identify the responsive transcriptional regulator. The effect of various deletions and mutations within the 5'-flanking region of the human MnSOD gene promoter was evaluated using the luciferase reporter system in A549 human lung carcinoma cells. Deletion of a region between -1292 and -1202 nucleotides upstream of the transcription start site abolished TPA-responsive induction, whereas deletion of the putative binding sequence for NF-kappaB or AP-1 did not. The region between -1292 and -1202 contains a cAMP-responsive element-like sequence, TGACGTCT, which we identified as the manganese superoxide dismutase TPA-responsive element, MSTRE. Site-specific mutation of the MSTRE abolished the TPA-responsive induction, validating the critical role of this sequence. We detected specific MSTRE activity from nuclear extracts and demonstrated by antibody supershift assay that this activity is closely related to CREB-1/ATF-1. TPA treatment rapidly induced phosphorylation of the CREB-1/ATF-1-like factor via the protein kinase C pathway. These results led us to conclude that the human MnSOD gene having the promoter construct used in this study is induced by TPA via activation of a CREB-1/ATF-1-like factor and not via either NF-kappaB or AP-1. In addition, we found that this induction was blocked by inhibitors of flavoproteins and NADPH oxidases, indicating involvement of enhanced generation of superoxide radical anion as an upstream signal.
 ...
PMID:Transcriptional activation of the human manganese superoxide dismutase gene mediated by tetradecanoylphorbol acetate. 1060 19

Accumulating evidence suggests that neuroepithelial bodies are airway O(2) sensors. Recently, we have established the H-146 small cell lung carcinoma line as a suitable model to study the biochemical basis of neuroepithelial body cell chemotransduction. Here we explore the possibility that hypoxic modulation of K(+) channels is intimately linked to activity of NADPH oxidase. Graded hypoxia caused graded inhibition of whole cell K(+) currents, which correlated well with membrane depolarization. Pretreatment with the phorbol ester, 12-O-tetradecanoyl (TPA), inhibited K(+) currents at all potentials. Although 4alpha-phorbol 12,13-didecanoate and TPA in the presence of bisindolylmaleimide were also able to depress K(+) currents, only TPA could significantly ameliorate hypoxic depression of these currents. Thus, protein kinase C (PKC) activation modulates the sensitivity of these cells to changes in pO(2). Furthermore, because the addition of H(2)O(2), a downstream product of NADPH oxidase, could only activate K(+) currents during hypoxia (when endogenous H(2)O(2) production is suppressed), it appears likely that PKC modulates the affinity of NADPH oxidase for O(2) potentially via phosphorylation of the p47(phox) subunit, which is present in these cells. These data show that PKC is an important regulator of the O(2)-transduction pathway and suggests that NADPH oxidase represents a significant component of the airway O(2) sensor.
 ...
PMID:O(2) sensing by airway chemoreceptor-derived cells. Protein kinase c activation reveals functional evidence for involvement of NADPH oxidase. 1071 79

Transforming growth factor-beta (TGF-beta) is a potent inducer of numerous extracellular matrix components, largely through a transcriptional mechanism. To define the postreceptor signaling pathways used by TGF-beta in the induction of extracellular matrix gene expression, we have utilized the human lung carcinoma cell line, A549, in transfection experiments with the TGF-beta inducible reporter construct, p3TP-Lux. Previous work from this laboratory using pharmacologic agents suggested that a phosphatidylcholine-specific phospholipase C and protein kinase C may be involved in early aspects of TGF-beta signaling. Here we provide evidence that TGF-beta induces a rapid and transient increase in diacylglycerol (DAG) production. When cells transfected with the p3TP-Lux reporter plasmid are simultaneously treated with TGF-beta and a DAG kinase inhibitor, we observed a higher level of luciferase than with TGF-beta alone. We also find elevated levels of phosphocholine in cells following TGF-beta treatment. Further, exogenously added bacterial phosphatidylcholine phospholipase C (PC-PLC) is capable of inducing expression of the p3TP-Lux reporter to the same extent as TGF-beta indicating that the bacterial PC-PLC can mimic the TGF-beta effect. In contrast, neither hexanoyl sphingosine (a ceramide analogue) nor arachadonic acid induce expression of the p3TP-Lux reporter. Measurements with the fluorescent, calcium-sensitive dye, FURA2, indicated that there was no change in intracellular calcium in response to TGF-beta. Furthermore, buffering intracellular calcium with the calcium chelating agent BAPTA/AM failed to block TGF-beta induction of the p3TP-Lux reporter. Thus the TGF-beta signaling pathway appears to involve the production of diacylglycerol but is independent of calcium.
 ...
PMID:TGF-beta signaling in A549 lung carcinoma cells: lipid second messengers. 1086 56

Gap junctional intercellular communication (GJIC) and connexin expression are frequently decreased in neoplasia and may contribute to defective growth control and loss of differentiated functions. GJIC, in E9 mouse lung carcinoma cells and WB-aB1 neoplastic rat liver epithelial cells, was elevated by forced expression of the gap junction proteins, connexin43 (Cx43) and connexin32 (Cx32), respectively. Transfection of Cx43 into E9 cells increased fluorescent dye-coupling in the transfected clones, E9-2 and E9-3, to levels comparable to the nontransformed sibling cell line, E10, from which E9 cells originated. Transduction of Cx32 into WB-aB1 cells also increased dye-coupling in the clone, WB-a/32-10, to a level that was comparable to the nontransformed sibling cell line, WB-F344. The cell cycle distribution was also affected as a result of forced connexin expression. The percentage of cells in G(1)-phase increased and the percentage in S-phase decreased in E9-2 and WB-a/32-10 cells as compared to E9 and WB-aB1 cells. Concomitantly, these cells exhibited changes in G(1)-phase cell cycle regulators. E9-2 and WB-a/32-10 cells expressed significantly less cyclin D1 and more p27(kip-1) protein than E9 and WB-aB1 cells. Other growth-related properties (expression of platelet-derived growth factor receptor-beta, epidermal growth factor receptor, protein kinase C-alpha, protein kinase A regulatory subunit-Ialpha, and production of nitric oxide in response to a cocktail of pro-inflammatory cytokines) were minimally altered or unaffected. Thus, enhancement of connexin expression and GJIC in neoplastic mouse lung and rat liver epithelial cells restored G(1) growth control. This was associated with decreased expression of cyclin D1 and increased expression of p27(kip-1), but not with changes in other growth-related functions.
 ...
PMID:Growth inhibition in G(1) and altered expression of cyclin D1 and p27(kip-1 )after forced connexin expression in lung and liver carcinoma cells. 1097 73

1. This study demonstrated aloe-emodin- and emodin-induced apoptosis in lung carcinoma cell lines CH27 (human lung squamous carcinoma cell) and H460 (human lung non-small cell carcinoma cell). Aloe-emodin- and emodin-induced apoptosis was characterized by nuclear morphological changes and DNA fragmentation. 2. During apoptosis, an increase in cytochrome c of cytosolic fraction and activation of caspase-3, identified by the cleavage of its proform, were observed. 3. To elucidate whether the expression of protein kinase C (PKC) isozymes are involved in aloe-emodin- and emodin-induced apoptosis, this study examined the changes of PKC isozymes by Western blotting techniques during aloe-emodin- and emodin-induced apoptosis. 4. The expression of PKC isozymes involved in aloe-emodin- and emodin-induced apoptosis of CH27 and H460 cells. In this study, aloe-emodin and emodin induced the changes of each of PKC isozymes in CH27 and H460 cells. 5. The decrease in the expression of PKC delta and epsilon may play a critical role in aloe-emodin- and emodin-induced apoptosis in CH27 and H460 cells. 6. The present study also demonstrated that PKC stimulation occurs at a site downstream of caspase-3 in the emodin-mediated apoptotic pathway.
 ...
PMID:Protein kinase C involvement in aloe-emodin- and emodin-induced apoptosis in lung carcinoma cell. 1168 58

Protein kinase C, a family of serine-threonine protein kinases, mediates a variety of intracellular signaling events. Here, the regulatory effect of phorbol 12-myristate 13-acetate(PMA)on the several PKC isozymes in the human lung carcinoma cells A-549 was studied. The expression of PKC-alpha PKC-betaII PKC-gamma PKC-delta and PKC-epsilon in A-549 cells was examined. No detectable PKC-zeta was observed. Short-term treatment of cells with PMA led to the translocation of these PKC isozymes, to different extent, from cytosol to cell membrane. Whereas, prolonged treatment of cells with PMA pronouncedly reduced the levels of PKC-alpha PKC-gamma PKC-delta and PKC-epsilon, but the intracellular level of PKC-betaII was not affected. Furthermore, PMA was observed to have differential effects on the down-regulation of PKC isozymes located in the cytosol and of those located in the membrane. Prolonged PMA treatment caused extensive decrease in the levels of cytosolic PKC-delta and PKC-gamma, and depleted cytosolic PKC-alpha and PKC-betaII. However, the amount levels of membrane PKC-alpha PKC-betaII PKC-gamma PKC-delta isozymes were not decreased. In contrast, PKC-epsilon in both cytosol and membrane fraction was obviously down-regulated by prolonged PMA treatment. This study provided novel evidence on the PMA-mediated activation and down-regulation of different PKC isozymes, which might be helpful in deepening our understanding on the roles of PKC activation and the alterations of their intracellular levels in processes of chemical carcinogenesis.
 ...
PMID:Regulation of Protein Kinase C in A-549 Cells by Phorbol Ester. 1205 80

There is very limited knowledge about the antibody response against tumor-expressed antigens in lung cancer. To arrive at a more complete picture of lung cancer antigens, we generated 2 cDNA libraries from squamous cell lung carcinoma and isolated 15 immunogenic antigens using autologous sera. Among the antigens most frequently identified were the lymphoid blast crisis oncogene (LBC), an unknown hypothetical protein and the p53-binding protein (TP53 BP), which have already been associated with tumor development. Of the immunogenic antigens, 6 map to chromosomes that are frequently altered in squamous cell lung carcinoma. SEREX database analysis showed that 7 of the identified immunogenic antigens have been associated with the humoral immune response in other human tumors. Screening with heterologous sera of patients with lung carcinoma identified 4 antigens, including human protein kinase C and TP53 BP, which have also been found by autologous screening. Only 1 of the 15 identified antigens reacted with any of the 36 control sera, which were taken from individuals without known disease. Sera from adenocarcinoma and large cell carcinoma of the lung were not reactive for the antigens. In summary, using 2 newly established cDNA libraries, we isolated 15 novel antigens, which were subsequently evaluated for the frequency of their corresponding antibodies in autologous, normal and heterologous sera; their chromosomal localization; and their correlation with survival after surgery.
 ...
PMID:Toward a more complete recognition of immunoreactive antigens in squamous cell lung carcinoma. 1240 7

Pulmonary neuroendocrine cells (PNECs) have been implicated in the development of small cell lung carcinoma (SCLC) and pediatric asthma, and smoking is a risk factor for both diseases. We as well as others have shown that the alpha(7) nicotinic acetylcholine receptor (alpha(7) nAChR) regulates the release of 5-hydroxytryptamine (5-HT, serotonin) in PNECs and SCLC. Serotonin is an autocrine growth factor for PNECs and SCLC and acts as broncho-constrictor. We found that nicotine and its nitrosated carcinogenic derivative 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) bind to the alpha(7) nAChR in SCLC and PNECs, resulting in the influx of Ca(2+), release of 5-HT, and activation of a mitogenic pathway mediated by protein kinase C (PKC), Raf-1, mitogen activated protein kinase (MAPK) and c-myc. Exposure to 10% CO(2) acted synergistically. Unstimulated SCLC cells from smokers demonstrated high base levels of 5-HT release and of individual downstream signaling components in comparison to PNECs. Subchronic exposure of PNECs to NNK up-regulated the alpha(7) nAChR and its associated serotonergic mitogenic pathway in PNECs, an effect that may contribute to the development of SCLC in smokers and pediatric asthma in children of mothers who smoke.
 ...
PMID:Receptor-mediated effects of nicotine and its nitrosated derivative NNK on pulmonary neuroendocrine cells. 1249 89

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine expressed in the non-small lung carcinoma cells (NSCLC). However, transcriptional regulation of GM-CSF is not well characterized in NSCLC. In this study we found that two cis-acting ETS family consensus sites are important for transcriptional regulation of GM-CSF in A549 human lung carcinoma cells. These two sites are located separately at around -40 and -100 bp from the transcription start site. Results of transient transfection assays with A549 cells indicated that ETS2 had a strong positive effect on GM-CSF promoter activity. Furthermore, this activity was enhanced by protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), in an ETS consensus-dependent manner, while PMA could also enhance the expression level of ETS2. The protein kinase C inhibitors decreased GM-CSF promoter activity induced by the protein kinase C activator PMA. We also found that antisense ETS2 mRNA decreased PMA-induced GM-CSF promoter activity, supporting the possibility that ETS2 is involved in protein kinase C-induced GM-CSF transcriptional function. Endogenous expression of GM-CSF mRNA was increased by ETS2 transfection and the increased expression was further enhanced by PMA. These data indicate that GM-CSF is up-regulated by ETS2, a target of protein kinase C.
 ...
PMID:ETS2 is involved in protein kinase C-activated expression of granulocyte-macrophage colony-stimulating factor in human non-small lung carcinoma cell line, A549. 1264 85


<< Previous 1 2 3 4 5 6 7 8 9 Next >>