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

The signal transducing regulatory protein (Gs alpha) was examined in B16 melanoma clones of low (F1C29) and high (F10C23) experimental metastatic potential. Incorporation of the photoaffinity analogue, [8-azido-gamma-32P]GTP, into Gs alpha was decreased in F10C23 extracts when compared to F1C29. This difference disappeared when the photolabeling reaction was carried out at an elevated temperature which enhanced the rate of GTP exchange, suggesting functional differences in the ability of Gs alpha to bind or release GTP rather than dissimilar intracellular Gs alpha concentrations. Differential Gs alpha photolabeling occurred only during the period of rapid growth when F10C23 cells proliferated faster than F1C29 cells. During the recovery phase of growth immediately following plating and at confluence, periods in which F1C29 and F10C23 growth rates are similar, Gs alpha photolabeling between the two clones was equal. CMT lung carcinoma clones of differential metastatic potential grew at a uniform rate at all stages of growth and also exhibited equal Gs alpha photolabeling. F10C23 cells were more responsive to alpha-melanocyte-stimulating hormone stimulation of adenylate cyclase activity than F1C29 cells at all growth stages. These results confirm previously observed functional differences in Gs alpha between B16 metastatic variants and show that photolabeling differences in Gs alpha are related to growth rate.
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PMID:Growth rate dependence of differential incorporation of a guanosine triphosphate photoaffinity probe into the alpha subunit of a guanine nucleotide binding protein, Gs, from metastatic variants of B16 melanoma cells. 254 98

Genetic defects in the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel, cause cystic fibrosis. Most defective forms of CFTR show improper intracellular trafficking. Because isoprenylated, small GTP-binding proteins are involved in the vesicular trafficking of other integral membrane proteins, we have investigated the role of isoprenylation in the trafficking of CFTR to the apical membranes of primary cultures of human airway epithelium and of Calu-3 cells, a human lung carcinoma cell line. CFTR function was measured as short circuit current, 125I efflux, and conductance of cell sheets with permeabilized basolateral membranes. Lovastatin, an inhibitor of isoprenyl lipid biosynthesis, markedly inhibited all measures of CFTR function. The lovastatin-induced declines in CFTR function were corrected by the simultaneous addition of mevalonate or the isoprenyl lipids geranylgeranyl and farnesyl but not cholesterol. Lovastatin reduced total cellular CFTR as assessed by immunoprecipitation. Mevalonate or isoprenyl lipids protected CFTR levels from the actions of lovastatin. Together, these results suggest a role for isoprenyl lipids, presumably through the actions of small GTP-binding proteins, in the trafficking of CFTR to the apical membrane of human airway epithelium.
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PMID:Effects of lovastatin on trafficking of cystic fibrosis transmembrane conductance regulator in human tracheal epithelium. 755 42

Previous reports have demonstrated that beta-endorphin stimulates the clonal growth of human small cell lung carcinoma (SCLC) cell lines. In this study, the human SCLC lines, NCI-H69, NCI-H345, and NCI-N417, were observed to be highly-enriched in saturable, high-affinity binding sites which are labeled by [125I]beta-endorphin. In contrast to conventional opioid receptors, [125I]beta-endorphin SCLC binding was insensitive to naloxone and other mu, delta, or kappa opioid ligands. Further analysis of the NCI-H69 cells demonstrated that specific (naloxone-insensitive) binding was dependent on receptor concentration, reversible, sensitive to sodium ion, but insensitive to the GTP analogue, Gpp(NH)p. These results suggest a role for naloxone-insensitive beta-endorphin in modulating SCLC metabolism.
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PMID:Human small cell lung cancer cells express high affinity naloxone-insensitive [125I]-endorphin binding sites. 783 28

For the sake of better understanding the molecular mechanism of neoplasia, we have used the mRNA differential display technique to analyze two human lung adenocarcinoma cell lines, AGZY83-a and Anip973. Anip973 was isolated from AGZY83-a, but manifested much higher metastatic potential than the parent line. We found that a significant differential cDNA fragment in Anip973 was over-expressed, then over-expressed cDNA fragment was cloned and sequenced. It showed that the over-expressed cDNA in Anip973 was RAB5A cDNA. And the RAB5A cDNA sequence was corresponding between the two cells. To determine whether RAB5A may be differentially expressed in the two human lung adenocarcinoma cells at protein level, we further detected RAB5A protein in the two cells by using immunofluorescent method. RAB5A protein was upregulated in highly metastatic Anip973. We also detected the difference in RAB5A gene expression at RNA level in human non-small cell lung carcinoma by RT-PCR. Using immunohistochemical staining, we also examined RAB5A change at protein level in 45 cases human non-small cell lung carcinoma paraffin sections. The results proved the evidence of upregulation of RAB5A in malignant tumor, indicated over-expression of RAB5A gene was correlated with the malignant degree and metastatic potential of lung cancer(chi2 test, p < 0.01). The RAB5A gene is a member of RAS superfamily, which can transcribe GTP-binding protein that plays an important role in signal transduction of protein trafficking at the cell surface and GDP/GTP cycle in the regulation of endocytotic membrane traffic. Thus our results indicated that overexpression of the RAB5A gene was involved in the process of transformation from AGZY83-a to the higher metastatic cell line Anip973. The result may be a powerful experimental evidence that over-expression of RAB5A gene associated with neoplasia metastasis.
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PMID:Differential expression of RAB5A in human lung adenocarcinoma cells with different metastasis potential. 1043 6

Tricyclic pyrones (TPs) may represent a novel synthetic class of microtubule (MT) de-stabilizing anticancer drugs previously shown by us to inhibit macromolecule synthesis, tubulin polymerization, and the proliferation of leukemic and mammary tumor cells in vitro. A linear skeleton with a N-containing aromatic ring attached at C3 of the top A-ring, a central pyran B-ring and a six-membered bottom C-ring with no alkylation at C7 are required for the antitumor activities of the lead compounds, a 3-pyridyl benzopyran (code name H10) and its somewhat weaker 2-pyridyl regioisomer (code name H19). Increasing concentrations of H10 do not alter the binding of [3H]vinblastine and [3H]GTP to tubulin but mimic the ability of unlabeled colchicine (CLC) to reduce the amount of [3H]CLC bound to tubulin, suggesting that TPs may interact with the CLC binding site to inhibit tubulin polymerization. Exogenous Mg2+ cations absolutely required for the binding of GTP to tubulin and MT assembly cannot overcome the antitubulin action of H10. H10 reduces the viability of L1210 cells in vitro (IC50: 0.5 microM) but its antitumor activity may be related to its ability to inhibit tubulin polymerization and rapidly increase the mitotic index rather than to induce DNA cleavage and apoptosis. The anticancer potential of TPs in vivo is demonstrated by the fact that i.p. injections of the water-soluble H10-HCl decrease the growth of solid tumors in mice inoculated s.c. with Lewis lung carcinoma. A critical finding is that the antimitotic H10 is a bifunctional anticancer drug, which also blocks the cellular transport of nucleosides (IC50: 6 microM) to inhibit DNA synthesis. Since few CLC site-binding antimitotic agents are active in solid tumor models in vivo, the ability of these new MT destabilizing TPs to totally block nucleoside transport might be valuable in polychemotherapy to arrest tumor cells at several phases of their cycle, potentiate the action of antimetabolites and sensitize multidrug-resistant tumor cells.
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PMID:Tricyclic pyrone analogs: a new synthetic class of bifunctional anticancer drugs that inhibit nucleoside transport, microtubule assembly, the viability of leukemic cells in vitro and the growth of solid tumors in vivo. 1047 69

mRNA differential display was applied to three small cell lung carcinoma (SCLC) cell lines, six non-small cell lung carcinoma (NSCLC) cell lines, and three normal lung tissues to identify genes differentially expressed between lung carcinoma cells and normal lung tissues and between SCLC cells and NSCLC cells. We isolated five differentially expressed genes, two that were novel and three that were already known. DIL-1 (differentially expressed in cancerous and noncancerous lung cells; HGMW-approved symbol SPON2) and pulmonary surfactant apoprotein A were expressed in normal lung tissues but not in lung carcinoma cell lines, whereas DIL-2 (HGMW-approved symbol C20orf2) and nm23-H1 were expressed in lung carcinoma cell lines but not in normal lung tissues. The remaining gene, Annexin II, was expressed at a lower level in SCLC than in NSCLC and normal lung tissues. These genes were also differentially expressed in primary lung cancers. One of the two novel genes, DIL-1, encodes a secreted protein homologous to the Mindin/F-spondin family. The other, DIL-2, encodes a protein with a putative ATP/GTP binding site motif. These data provide basic information necessary to understand the differences in gene expression profiles between lung carcinoma and normal lung and between SCLC and NSCLC. Further characterization of these genes will help to clarify the molecular mechanisms of human lung carcinogenesis.
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PMID:Identification of genes (SPON2 and C20orf2) differentially expressed between cancerous and noncancerous lung cells by mRNA differential display. 1051 75

Recently, several studies have suggested that a major mechanism of resistance to paclitaxel might involve mutations in the beta-tubulin gene in tumor cells. To investigate the frequency of beta-tubulin mutations in Japanese patients with small and non-small cell lung cancer, direct sequence analysis following reverse transcription-polymerase chain reaction (RT-PCR) of the beta-tubulin gene was performed using total RNA from 20 lung cancer cell lines and 22 specimens from lung cancer patients. First-strand cDNA sequence analysis of the 42 samples showed silent mutations at codon 180 of the beta-tubulin gene, which encodes the GTP-binding site of the protein, and codons 195 and 217. However, neither missense nor non-sense mutations affecting microtubule dynamics, within or near the GTP-binding site of the beta-tubulin gene, were detected. These results indicate that beta-tubulin gene mutations might not play a major role in the mechanism of resistance to paclitaxel in Japanese lung cancer patients. Further investigations are needed to clarify the mechanism of drug resistance.
Lung Cancer 2002 Jan
PMID:Mutational analysis of the beta-tubulin gene in lung cancer. 1236 1

RhoE, a small G protein, is constitutively GTP bound within the cell and can regulate actin cytoskeleton reorganization, leading to the appearance of aggregates of actin filaments. Although emerging evidence suggests that RhoE is causally involved in cancer formation and progression, little is known about its significance in solid cancer, including lung cancer. In the present study, the expression of RhoE was analyzed using Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR), real-time RT-PCR, immunohistochemistry and western blot in 30 patients with Non-small Cell Lung Cancer (NSCLC). Then the correlation of RhoE overexpression with clinical parameters was evaluated. Furthermore, the possible reasons contributing to the RhoE expression were examined by real-time genomic PCR and mutation analysis on DNA sequence and cDNA sequence. Our results revealed that RhoE expression was dramatically increased in lung cancer tissues compared with adjacent nontumoral lung tissues (p <0.01). Immunohistochemistry showed a strong cytoplasmic staining in cancer cells compared with positive membrane staining in adjacent nontumoral proliferative alveolar epitheliums. Moreover, the overexpression of RhoE was significantly associated with the patients' smoking history (p <0.05). 72% tumor tissues displayed DNA copy number changes based on the DNA levels in the matched adjacent nontumoral lung tissues and this copy number changes correlated significantly with RhoE expression and smoking history (p <0.05). Three polymorphisms were identified but no correlation was found with the clinicopathological features. To our knowledge, this is the first report demonstrating that overexpression of RhoE correlated with smoking and DNA copy number changes, suggesting that RhoE may serve as a molecular marker to identify high-risk individuals and assist in the identification of additional pathways of carcinogenesis.
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PMID:Overexpression of RhoE in Non-small Cell Lung Cancer (NSCLC) is associated with smoking and correlates with DNA copy number changes. 1731 84

It has been proposed that the metastasis suppressor CD82/KAI-1, which is a member of the tetraspanin superfamily, regulates biological activity by associating with cell surface receptors or proteins. We show a novel association between CD82 and the hepatocyte growth factor (HGF) receptor c-Met. Although ectopic expression of CD82 in nonsmall cell lung carcinoma cells did not affect the tyrosine phosphorylation of c-Met, these cells showed significant suppression of HGF-induced lamellipodial protrusion and cell migration. CD82 selectively attenuated c-Met signaling via the Ras-Cdc42/Rac and the phosphatidylinositol 3-kinase/Cdc42/Rac pathways. In contrast, another c-Met signaling pathway that involves phosphatidylinositol 3-kinase/Akt and phosphatidylinositol 3-kinase/mitogen activated protein kinase was not affected by CD82. Signaling adapter proteins for c-Met, such as Grb2 and p85, exhibited reduced association with c-Met in cells that ectopically expressed CD82. These results indicate that the CD82-c-Met complex inhibits HGF-induced cancer cell migration by the inactivation of small GTP-binding proteins of the Rho family via c-Met adapter proteins.
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PMID:Regulation of c-Met signaling by the tetraspanin KAI-1/CD82 affects cancer cell migration. 1762 32

The GIMAP (GTPase of the immunity-associated protein) gene family includes seven functional members residing on human chromosome 7. GIMAP genes encode GTP-binding proteins that share a unique primary structure and whose function is largely unknown. However, gene ablation studies reveal that Gimap4 plays an important role in regulating the apoptosis of T cells. In a pilot microarray analysis on six cases of non-small cell lung cancer (NSCLC), we discovered that the expression of GIMAP family members, but not the neighboring non-GIMAP genes, was uniformly lower in the tumor tissues, compared to that in the adjacent nontumor tissues. This finding was subsequently confirmed by quantitative PCR assays in a total of twenty NSCLCs, and we found that GIMAP6 and GIMAP8 showed striking reduction of gene expression in the tumors. In contrast, GIMAP8 mRNA level was abnormally elevated in the adjacent nontumor tissues as compared to that in the control lung tissues. Such reciprocal expression of GIMAPs suggests that this unique gene family might contribute to the pathogenesis of and immune reactions to NSCLC.
Lung Cancer 2008 Dec
PMID:Dysregulation of GIMAP genes in non-small cell lung cancer. 1846 27


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