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)

Phosphoinositide 3-kinase (PI 3-K) is implicated in a wide array of biological and pathophysiological responses, including tumorigenesis, invasion and metastasis, therefore specific inhibitors of the kinase may prove useful in cancer therapy. We propose that specific inositol polyphosphates have the potential to antagonize the activation of PI 3-K pathways by competing with the binding of PtdIns(3,4,5)P3 to pleckstrin homology (PH) domains. Here we show that Ins(1,3,4,5,6)P5 inhibits the serine phosphorylation and the kinase activity of Akt/PKB. As a consequence of this inhibition, Ins(1,3,4,5,6)P5 induces apoptosis in ovarian, lung and breast cancer cells. Overexpression of constitutively active Akt protects SKBR-3 cells from Ins(1,3,4,5,6)P5-induced apoptosis. Furthermore, Ins(1,3,4,5,6)P5 enhances the proapoptotic effect of cisplatin and etoposide in ovarian and lung cancer cells, respectively. These results support a role for Ins(1,3,4,5,6)P5 as a specific inhibitor of the PI 3-K/Akt signalling pathway, that may sensitize cancer cells to the action of commonly used anticancer drugs.
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PMID:Inositol pentakisphosphate promotes apoptosis through the PI 3-K/Akt pathway. 1475 53

We have previously observed the suppression of lung tumor growth in response to overexpression of melanoma differentiation-associated gene-7 (MDA-7)/interleukin-24 (IL-24; approved gene symbol IL24) in vitro and in vivo. MDA-7/IL-24 exerts its tumor-suppressive effects by multiple mechanisms, including the activation of the caspase cascade and the inhibition of angiogenesis. In this study, we used an adenoviral vector (Ad-mda7) to examine the effect of the ectopic production of MDA-7/IL-24 on cell migration and invasion by human non-small-cell lung carcinoma cells. Lung tumor cells (H1299 and A549) treated in vitro with Ad-mda7 migrated and invaded less than cells treated with phosphate-buffered saline (PBS) or Ad-Luc (vector control). MDA-7/IL-24 inhibited migration and invasion by down-regulating the production of phosphatidylinositol 3-kinase/protein kinase B, focal adhesion kinase, and matrix metalloproteinase-2 and -9 relative to PBS and Ad-Luc. Furthermore, tumor cells treated with Ad-mda7 ex vivo or with DOTAP:Chol-mda7 complex in vivo formed significantly fewer tumors in an experimental lung metastasis model. These results show that MDA-7/IL-24 inhibits invasion and migration by lung cancer cells by down-regulating proteins associated with these processes, resulting in reduced metastasis. Thus, Ad-mda7 should be considered a therapeutic agent that can inhibit primary tumor growth and prevent metastasis.
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PMID:Ectopic production of MDA-7/IL-24 inhibits invasion and migration of human lung cancer cells. 1509 81

Caveolin-1 (CAV1), an essential structural constituent of caveolae that plays an important role in cellular processes such as transport and signaling, has been implicated in the development of human cancers. However, it is unclear whether CAV1 is acting like an oncogene or tumor suppressor gene. We found that CAV1 expression was reduced or absent in 95% of small cell lung cancers (SCLCs; n = 21 lines), whereas it was retained in 76% of non-small cell lung cancers (NSCLCs; n = 25 lines) compared with normal human lung epithelial cultures, where it was abundantly expressed. CAV1 expression was tightly linked to the ability to grow attached to the plastic cell culture surface, whereas CAV1-nonexpressing lung cancers of both SCLC and NSCLC type grew as suspension cultures. In addition, attached lung cancer cultures expressed phosphorylated focal adhesion kinase, whereas suspension cultures did not. Lack of CAV1 expression was tightly associated with CAV1 promoter methylation (P < 0.0001) such that CAV1 methylation was found in 93% of SCLCs (n = 15) and 9% of NSCLCs (n = 11), whereas 5-aza-2'deoxycytidine treatment restored CAV1 expression in SCLCs. Exogenous CAV1 expression in SCLCs significantly inhibited soft-agar colony formation but did not lead to attachment. By contrast, CAV1 knockdown in NSCLCs mediated by small interfering RNA against CAV1 led to inhibition of cellular proliferation and soft-agar and liquid colony formation. Importantly, CAV1 knockdown led to reduced phospho-focal adhesion kinase and RalA, but not RalB, levels in NSCLC cells. These results suggest different roles for CAV1 in SCLC, where CAV1 acts like a tumor suppressor gene, and NSCLC, where it appears required for survival and growth.
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PMID:Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer. 1520 42

The identification of genes undergoing genetic or epigenetic alterations and contributing to the development of cancer is critical to our understanding of the molecular mechanisms of carcinogenesis. A new approach in identifying alterations of genes that might be relevant to the process of tumor development was used in this study by examining the gene expression profile in human lung cancer cells exposed to 5-aza-2'-deoxycytidine (5-aza-dC). A cDNA array analysis was carried out on 5-aza-dC-treated and untreated non small cell lung cancer (NSCLC) cell line NCI-H522. Sixteen and 14 genes were upregulated and downregulated, respectively, by 5-aza-dC treatment. Among them, downregulation of tyrosine protein kinase ABL2 (ABL2) gene and upregulation of hint/protein kinase C inhibitor 1 (Hint/PKCI-1), DVL1, TIMP-1, and TRP-1 genes were found in expanded observations in two or three of five 5-aza-dC-treated NSCLC cell lines. Among these genes, we found that cDNA transfer of Hint/PKCI-1 resulted in a significant in vitro growth inhibition in two cell lines exhibiting 5-aza-dC-induced upregulation of Hint/PKCI-1 and significantly reduced in vivo tumorigenicity of one NSCLC cell line. Hint/PKCI-1, which is the only other characterized human histidine triad (HIT) nucleotide-binding protein in addition to tumor-suppressor gene FHIT, might be involved in lung carcinogenesis.
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PMID:Aberrant gene expression in human non small cell lung carcinoma cells exposed to demethylating agent 5-aza-2'-deoxycytidine. 1525 63

Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) plays an essential role in angiogenesis and development. It is differentially expressed in tumor cell lines, but its role in carcinogenesis is largely unknown. We demonstrate here that noninvasive human lung cancer cells become invasive when COUP-TFII was expressed. The expression of extracellular matrix degrading proteinases, such as matrix metalloproteinase 2 and urokinase-type plasminogen activator, was up-regulated in these cells. This finding was confirmed by transduction of different human lung cancer cell lines with COUP-TFII protein and also by using antisense expression. We observed disorganization of actin filaments and focal adhesion kinase phosphorylation in COUP-TFII-transfected human lung cancer cells in addition to the increase in extracellular metalloproteinase activity. These results suggest that COUP-TFII may be considered as a new target for anticancer therapies.
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PMID:Expression of chicken ovalbumin upstream promoter-transcription factor II enhances invasiveness of human lung carcinoma cells. 1528 11

In contrast to the spectrum of biochemical analyses of fresh material, that of archived specimens is widely restricted. Fixation of specimens with formalin, the most commonly used fixative, usually prevents further molecular analysis, since it leads to degradation of nucleic acids and denaturation of the antigenic determinants of proteins. To overcome these problems, the Hepes-glutamic acid buffer mediated Organic solvent Protection Effect (HOPE)-fixation technique has been developed, which preserves nucleic acids and antigenic determinants of proteins, thus expanding the applicability of immunohistochemical methods. In this study, we investigated whether HOPE-fixed tissue can be analyzed by Western blotting. Furthermore, a comparison with conventionally fixed and frozen material was made. The specimens used were tumor-free and obtained from lobectomies for lung cancer. All four antibodies tested, i.e., antibodies specific for focal adhesion kinase, surfactant protein A, PI-3-kinase, and IKKalpha, worked well if used for immunoblotting of HOPE-fixed and frozen tissue. By contrast, these antibodies showed no or only very weak specific binding if formalin-fixed specimens were analyzed. Our findings show that HOPE fixation maintains the antigenicity of proteins better than formalin fixation. The possibility for performing Western blotting with archived paraffin-embedded specimens extends the options for diagnostic and scientific analyses of fixed tissues.
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PMID:HOPE technique enables Western blot analysis from paraffin-embedded tissues. 1531 Jan 50

Exposure to particulate matter (PM) is associated with several health effects including lung cancer. However, the mechanisms of particle-induced carcinogenesis are not fully understood. The main aim of this study was to investigate the genotoxicity of PM in relation to particle-cell interactions and to study the effect of removal of DNA-damaging substances by extraction of PM with different solvents. Genotoxicity was analyzed by means of the comet assay after exposure of cultured human fibroblasts to urban dust particles (SRM 1649). It was found that PM induced DNA damage in a dose-dependent manner and that cells interacting with PM suffered more DNA single-strand breaks relative to other cells. The genotoxicity of PM was significantly reduced after extraction with dichloromethane (DCM), dimethyl sulfoxide (DMSO) and water, but not with acetone and hexane. However, the insoluble particle core still induced DNA single-strand breaks. The extracts were further investigated in cell-free systems. Analysis of aromatic DNA adducts with 32P-HPLC showed that the DMSO and DCM extracts contained most of the DNA-reactive polyaromatic compounds (PACs). Further, the formation of 8-oxo-2'-deoxyguanosine (8-oxodG) upon incubation of the extracts with 2'-deoxyguanosine (dG) showed that the water extract contained most of the oxidizing substances. Thus, the genotoxicity of PM was caused both by adduct-forming PACs and oxidizing substances as well as the insoluble particle-core. This study showed that all these factors together contribute to explaining the mechanisms of PM genotoxicity.
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PMID:Genotoxicity of airborne particulate matter: the role of cell-particle interaction and of substances with adduct-forming and oxidizing capacity. 1557 34

Imatinib mesylate, an inhibitor of tyrosine kinases including BCR-ABL and KIT, inhibits the growth inhibition of small cell lung cancer (SCLC) cell lines in vitro. However, clinical trials of imatinib mesylate alone in patients with SCLC resulted in unsatisfactory outcomes. Vitamin K2 (menaquinone-4: VK2) induces apoptosis and differentiation in leukemia cells. We recently reported that VK2 also induces apoptosis in lung cancer cell lines. In the present study, we focused on the in vitro combined effects of imatinib mesylate plus VK2 on SCLC cell lines such as LU-139, LU-130, NCI-H69 and NCI-H128. Treatment with imatinib mesylate and VK2 for 96 h resulted in suppression of cell growth in a dose-dependent manner in all cell lines tested. The 50% inhibitory concentration (IC50) for imatinib mesylate ranged from 17-29 microM, whereas the IC50 for VK2 ranged from 16-64 microM. Combined treatment of imatinib mesylate plus VK2 resulted in pronounced inhibition of cell growth. The morphologic features of cells treated with imatinib mesylate and VK2 were typical of apoptosis. Since VK2 is a safe medicine without prominent adverse effects, treatment of patients with SCLC could derive therapeutic benefits from a combination of imatinib mesylate and VK2.
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PMID:Combination of vitamin K2 plus imatinib mesylate enhances induction of apoptosis in small cell lung cancer cell lines. 1558 22

The elevated levels of beta1,4-galactosyltransferase I (GalT I; EC 2.4.1.38) are detected in highly metastatic lung cancer PGBE1 cells compared with its less metastatic partner PGLH7 cells. Decreasing the GalT I surface expression by small interfering RNA or interfering with the surface of GalT I function by mutation inhibited cell adhesion on laminin, the invasive potential in vitro, and tyrosine phosphorylation of focal adhesion kinase. The mechanism by which GalT I activity is up-regulated in highly metastatic cells remains unclear. To investigate the regulation of GalT I expression, we cloned the 5'-region flanking the transcription start point of the GalT I gene (-1653 to +52). Cotransfection of the GalT I promoter/luciferase reporter and the Ets family protein E1AF expression plasmid increased the luciferase reporter activity in a dose-dependent manner. By deletion and mutation analyses, we identified an Ets-binding site between nucleotides -205 and -200 in the GalT I promoter that was critical for responsiveness to E1AF. It was identified that E1AF could bind to and activate the GalT I promoter by electrophoretic mobility shift assay in PGLH7 cells and COS1 cells. A stronger affinity of E1AF for DNA has contributed to the elevated expression of GalT I in PGBE1 cells. Stable transfection of the E1AF expression plasmid resulted in increased GalT I expression in PGLH7 cells, and stable transfectants migrated faster than control cells. Meanwhile, the content of the beta1,4-Gal branch on the cell surface was increased in stably transfected PGLH7 cells. GalT I expression can also be induced by epidermal growth factor and dominant active Ras, JNK1, and ERK1. These data suggest an essential role for E1AF in the activation of the human GalT I gene in highly metastatic lung cancer cells.
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PMID:Elevated beta1,4-galactosyltransferase I in highly metastatic human lung cancer cells. Identification of E1AF as important transcription activator. 1561 Nov 27

The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes to the points of cell contact with the extracellular matrix, called focal adhesions. Many factors induce tyrosine phosphorylation of FAK including growth factors, neuropeptides and integrin-dependent adhesion to the extracellular matrix. FAK has been implicated in several cellular processes such as invasion, motility, proliferation and apoptosis. In addition, FAK expression was shown to be elevated in a number of different human cancers, suggesting a role in the development of malignancy. We examined the biological functions of FAK using small inhibitory RNAs (siRNA) in cancer cells. Although FAK siRNA reduced the FAK protein levels by approximately 70% in several cancer cell lines, there was no clear evidence of apoptosis. However, in clonogenic and soft-agar assays in H1299, a lung cancer cell line, FAK siRNA treatment led to a 43% to 55% decrease in colony formation. Furthermore, FAK siRNA-treated cells displayed a decrease in migration when serum or EGF (epidermal growth factor) were used as chemo-attractants. Our results demonstrated that inhibition of FAK protein leads to alterations in cell growth and migration.
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PMID:Functional analysis of focal adhesion kinase (FAK) reduction by small inhibitory RNAs. 1573 29


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