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)

RECK is a membrane-anchored glycoprotein that may negatively regulate matrix metalloproteinase activity to suppress tumor invasion and metastasis. Our previous study indicated that oncogenic RAS inhibited RECK expression via a histone deacetylation mechanism. In this study, we address whether DNA methyltransferases (DNMT) participate in the inhibition of RECK by RAS. Induction of Ha-RAS(Val12) oncogene increased DNMT3b, but not DNMT1 and DNMT3a, expression in 2-12 cells. In addition, induction of DNMT3b by RAS was through the extracellular signal-regulated kinase signaling pathway. Oncogenic RAS increased the binding of DNMT3b to the promoter of RECK gene and this binding induced promoter methylation, which could be reversed by 5'-azacytidine and DNMT3b small interfering RNA (siRNA). The MEK inhibitor U0126 also reversed RAS-induced DNMT3b binding and RECK promoter methylation. Treatment of 5'-azacytidine and DNMT3b siRNA restored RECK expression in 2-12 cells and potently suppressed RAS-stimulated cell invasion. In addition, the inhibitory effect of 5'-azacytidine on RAS-induced cell invasion was attenuated after knockdown of RECK by siRNA. Interestingly, human lung cancer cells harboring constitutively activated RAS exhibited lower RECK expression and higher promoter methylation of RECK gene. 5'-Azacytidine and DNMT3b siRNA restored RECK expression in these cells and effectively suppressed invasiveness. Collectively, our results suggest that RAS oncogene induces RECK gene silencing through DNMT3b-mediated promoter methylation, and DNMT inhibitors may be useful for the treatment of RAS-induced metastasis.
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PMID:Silencing of the metastasis suppressor RECK by RAS oncogene is mediated by DNA methyltransferase 3b-induced promoter methylation. 1695 Nov 51

Genetic knock out of the transcriptional co-repressor carboxyl-terminal-binding protein (CtBP) in mouse embryonic fibroblasts results in up-regulation of several genes involved in apoptosis. We predicted, therefore, that a propensity toward apoptosis might be regulated through changes in cellular CtBP levels. Previously, we have identified the homeodomain-interacting protein kinase 2 as such a regulator and demonstrated that HIPK2 activation causes Ser-422 phosphorylation and degradation of CtBP. In this study, we found that c-Jun NH2-terminal kinase 1 activation triggered CtBP phosphorylation on Ser-422 and subsequent degradation, inducing p53-independent apoptosis in human lung cancer cells. JNK1 has previously been linked to UV-directed apoptosis. Expression of MKK7-JNK1 or exposure to UV irradiation reduced cellular levels of CtBP via a proteasome-mediated pathway. This effect was prevented by JNK1 deficiency. In addition, sustained activation of the JNK1 pathway by cisplatin similarly triggered CtBP degradation. These findings provide a novel target for chemotherapy in cancers lacking p53.
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PMID:c-Jun NH2-terminal kinase promotes apoptosis by down-regulating the transcriptional co-repressor CtBP. 1698 92

Analysis of lung cancer response to chemotherapeutic agents showed the accumulation of a Taxol-induced protein that reacted with an anti-phospho-MEK1/2 antibody. Mass spectroscopy identified the protein as nucleophosmin/B23 (NPM), a multifunctional protein with diverse roles: ribosome biosynthesis, p53 regulation, nuclear-cytoplasmic shuttling, and centrosome duplication. Our work demonstrates that following cellular exposure to mitosis-arresting agents, NPM is phosphorylated and its chromatographic property is altered, suggesting changes in function during mitosis. To determine the functional relevance of NPM, its expression in tumor cells was reduced by siRNA. Cells with reduced NPM were treated with Taxol followed by microarray profiling accompanied by gene/protein pathway analyses. These studies demonstrate several expected and unexpected consequences of NPM depletion. The predominant downstream effectors of NPM are genes involved in cell proliferation, cancer, and the cell cycle. In congruence with its role in cancer, NPM is over-expressed in primary malignant lung cancer tissues. We also demonstrate a role for NPM in the expression of genes encoding SET (TAF1beta) and the histone methylase SET8. Additionally, we show that NPM is required for a previously unobserved G2/M upregulation of TAF1A, which encodes the rDNA transcription factor TAF(I)48. These results demonstrate multi-faceted functions of NPM that can affect cancer cells.
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PMID:Global functional analysis of nucleophosmin in Taxol response, cancer, chromatin regulation, and ribosomal DNA transcription. 1706 96

Papillary thyroid carcinoma (PTC) is the most frequent malignant neoplasm of the thyroid originating from the thyroid follicular cell (TFC). Although the formation of PTC is believed to result from rearrangements of RET or TRK oncogenes or MET point mutations, these structural aberrations or point mutations do not correlate with the clinicopathological features of PTC and do not seem to be a useful prognostic marker of the disease. Therefore, further experiments should be carried out in order to find new practical clinical markers. Recently, oncogene BRAF has become a subject of great interest. The mutation of BRAF gene is characteristic for PTC and poorly differentiated and/or undifferentiated cancers derived from PTC. The occurrence of BRAF mutation has often been observed in various human tumours. The presence of mutation was confirmed in melanoma, colon cancer, gliomas and lung cancer. In the majority of cases, there is only one type of point mutation - V600E. The RAS/RAF/MEK/MAPK kinase pathway mediates the cellular response to mitogenic signals. BRAF gene mutation results in increased kinase activity, leading to excessive activation of the above mitogenic pathway and to uncontrolled proliferation of cancer cells. Some correlation was noticed between BRAF gene mutation and the clinical stage of the neoplastic disease in question. Preliminary investigations indicate that the presence of BRAF mutation might be a valuable diagnostic and prognostic marker of the disease. Further investigations could also bring further improvements into the therapeutic management of thyroid cancer. There are reports emphasizing the possibility of using the inhibitors of BRAF proteins in the treatment of PTC. Certainly, in order to confirm the diagnostic usefulness of this marker, further studies should be carried out.
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PMID:BRAF mutations in papillary thyroid carcinoma. 1720 87

Aberrant intracellular signaling resulting from mutations and oncogenic activation, as well as gene amplification of critical proteins involved in signal transduction pathways, are key features of lung cancer. Three important intracellular signaling proteins, the mammalian target of rapamycin, protein kinase B, and mitogen-activated protein kinase kinase have emerged as attractive targets for lung cancer therapy. We review current information on the therapeutic manipulation of these targets and describe early clinical data in lung cancer.
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PMID:The Akt/mTOR and mitogen-activated protein kinase pathways in lung cancer therapy. 1740 53

Mutations in the BRAF and KRAS genes occur in approximately 1% to 2% and 20% to 30% of non-small-cell lung cancer patients, respectively, suggesting that the mitogen-activated protein kinase (MAPK) pathway is preferentially activated in lung cancers. Here, we show that lung-specific expression of the BRAF V600E mutant induces the activation of extracellular signal-regulated kinase (ERK)-1/2 (MAPK) pathway and the development of lung adenocarcinoma with bronchioloalveolar carcinoma features in vivo. Deinduction of transgene expression led to dramatic tumor regression, paralleled by dramatic dephosphorylation of ERK1/2, implying a dependency of BRAF-mutant lung tumors on the MAPK pathway. Accordingly, in vivo pharmacologic inhibition of MAPK/ERK kinase (MEK; MAPKK) using a specific MEK inhibitor, CI-1040, induced tumor regression associated with inhibition of cell proliferation and induction of apoptosis in these de novo lung tumors. CI-1040 treatment also led to dramatic tumor shrinkage in murine lung tumors driven by a mutant KRas allele. Thus, somatic mutations in different signaling intermediates of the same pathway induce exquisite dependency on a shared downstream effector. These results unveil a potential common vulnerability of BRAF and KRas mutant lung tumors that potentially affects rational deployment of MEK targeted therapies to non-small-cell lung cancer patients.
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PMID:Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models. 1751 Apr 23

Intrinsic resistance to the epidermal growth factor receptor (EGFR; HER1) tyrosine kinase inhibitor (TKI) gefitinib, and more generally to EGFR TKIs, is a common phenomenon in breast cancer. The availability of molecular criteria for predicting sensitivity to EGFR-TKIs is, therefore, the most relevant issue for their correct use and for planning future research. Though it appears that in non-small-cell lung cancer (NSCLC) response to gefitinib is directly related to the occurrence of specific mutations in the EGFR TK domain, breast cancer patients cannot be selected for treatment with gefitinib on the same basis as such EGFR mutations have been reported neither in primary breast carcinomas nor in several breast cancer cell lines. Alternatively, there is a general agreement on the hypothesis that the occurrence of molecular alterations that activate transduction pathways downstream of EGFR (i.e., MEK1/MEK2 right curved arrow ERK1/2 MAPK and PI-3'K right curved arrow AKT growth/survival signaling cascades) significantly affect the response to EGFR TKIs in breast carcinomas. However, there are no studies so far addressing a role of EGF-related ligands as intrinsic breast cancer cell modulators of EGFR TKI efficacy. We recently monitored gene expression profiles and sub-cellular localization of HER-1/-2/-3/-4 related ligands (i.e., EGF, amphiregulin, transforming growth factor-alpha, beta-cellulin, epiregulin and neuregulins) prior to and after gefitinib treatment in a panel of human breast cancer cell lines. First, gefitinib-induced changes in the endogenous levels of EGF-related ligands correlated with the natural degree of breast cancer cell sensitivity to gefitinib. While breast cancer cells intrinsically resistant to gefitinib (IC50 > or =15 microM) markedly up-regulated (up to 600 times) the expression of genes codifying for HER-specific ligands, a significant down-regulation (up to 10(6) times) of HER ligand gene transcription was found in breast cancer cells intrinsically sensitive to gefitinib (IC50 < or =1 microM). Second, loss of HER1 function differentially regulated the nuclear trafficking of HER-related ligands. While gefitinib treatment induced an active import and nuclear accumulation of the HER ligand NRG in intrinsically gefitinib-resistant breast cancer cells, an active export and nuclear loss of NRG was observed in intrinsically gefitinib-sensitive breast cancer cells. In summary, through in vitro and pharmacodynamic studies we have learned that, besides mutations in the HER1 gene, oncogenic changes downstream of HER1 are the key players regulating gefitinib efficacy in breast cancer cells. It now appears that pharmacological inhibition of HER1 function also leads to striking changes in both the gene expression and the nucleo-cytoplasmic trafficking of HER-specific ligands, and that this response correlates with the intrinsic degree of breast cancer sensitivity to the EGFR TKI gefitinib. The relevance of this previously unrecognized intracrine feedback to gefitinib warrants further studies as cancer cells could bypass the antiproliferative effects of HER1-targeted therapeutics without a need for the overexpression and/or activation of other HER family members and/or the activation of HER-driven downstream signaling cascades.
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PMID:An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: Gefitinib (Iressa) -induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review). 1754 82

Evidence indicates that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E2 (PGE2) levels contribute to the pathogenesis of non-small-cell lung cancer (NSCLC). In addition to overproduction by COX-2, PGE2 concentrations also depend upon the levels of the PGE2 catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH). We find a dramatic down-regulation of PGDH protein in NSCLC cell lines and in resected human tumors when compared with matched normal lung. Affymetrix array analysis of 10 normal lung tissue samples and 49 resected lung tumors revealed a much lower expression of PGDH transcripts in all NSCLC histologic groups. In addition, treatment with the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) erlotinib increased the expression of 15-PGDH in a subset of NSCLC cell lines. This effect may be due in part to an inhibition of the extracellular signal-regulated kinase (ERK) pathway as treatment with mitogen-activated protein kinase kinase (MEK) inhibitor U0126 mimics the erlotinib results. We show by quantitative reverse transcription-PCR that the transcript levels of ZEB1 and Slug transcriptional repressors are dramatically reduced in a responsive cell line upon EGFR and MEK/ERK inhibition. In addition, the Slug protein, but not ZEB1, binds to the PGDH promoter and represses transcription. As these repressors function by recruiting histone deacetylases to promoters, it is likely that PGDH is repressed by an epigenetic mechanism involving histone deacetylation, resulting in increased PGE2 activity in tumors. This effect is reversible in a subset of NSCLC upon treatment with an EGFR TKI.
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PMID:Inhibition of epidermal growth factor receptor signaling elevates 15-hydroxyprostaglandin dehydrogenase in non-small-cell lung cancer. 1757 21

Cyclooxygenase-2 (COX-2) is a key enzyme in the production of prostaglandins and thromboxanes from free arachidonic acid. Increasing evidence suggests that COX-2 plays a role in tumorigenesis. A variety of stimuli induce COX-2 and it is overexpressed in many tumors, including non-small cell lung cancer (NSCLC). We studied the regulation of COX-2 expression in immortalized human bronchial epithelial cells (HBECs) by transforming growth factor-beta1 (TGF-beta1) and epidermal growth factor (EGF) because these two growth factors are present in both the pulmonary milieu of those at risk for lung cancer as well as in the tumor microenvironment. EGF significantly enhanced TGF-beta1-mediated induction of COX-2 and corresponding prostaglandin E2 (PGE2) production. TGF-beta1 and EGF induced COX-2 at the transcriptional and post-transcriptional levels. EGF receptor (EGFR) inhibition, neutralizing antibody against amphiregulin, or mitogen-activated protein kinase kinase (MEK) inhibition blocked TGF-beta1-mediated COX-2 induction. COX-2 induction by TGF-beta1 depended upon Smad3 signaling and required the activity of EGFR or its downstream mediators. Autocrine amphiregulin signaling maintains EGFR in a constitutively active state in HBECs, allowing for COX-2 induction by TGF-beta1. Thus, EGFR ligands, which are abundant in the pulmonary microenvironment of those at risk for lung cancer, potentiate and are required for COX-2 induction by TGF-beta1 in HBEC. These findings emphasize the central role of EGFR signaling in COX-2 induction by TGF-beta1 and suggest that inhibition of EGFR signaling should be investigated further for lung cancer prevention.
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PMID:EGFR signaling is required for TGF-beta 1 mediated COX-2 induction in human bronchial epithelial cells. 1760 Mar 11

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


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