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)

Survivin is expressed in most cancers but is undetectable in differentiated adult cells, and plays an important role both in the suppression of apoptosis and mitotic spindle checkpoint; thus it has attracted great interest as a potential drug target. In this study, we investigated the antigene and antiproliferative effects of triplex-forming oligodeoxynucleotides (TFO) targeting survivin in human lung carcinoma A549 cells. Survivin-specific TFOs form stable triplexes under physiological conditions as tested by electrophoretic mobility shift assays. Treatment of A549 cells with survivin-specific but not control TFOs at a concentration of 400 nM in the presence of uptake-enhancing liposome significantly reduced survivin protein level, inhibited cell proliferation, and induced cell apoptosis as demonstrated by immunoblot, cell number counting, and Annexin V-staining. Moreover, we found that the triplex-forming potential of TFOs measured in vitro does not necessarily correlate with the ability of TFOs to affect expression of a targeted gene in vivo. Our results indicate that targeting survivin is a promising alternative strategy for the development of novel anticancer therapeutics.
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PMID:Triplex-forming oligodeoxynucleotides targeting survivin inhibit proliferation and induce apoptosis of human lung carcinoma cells. 1271 10

Survivin is an inhibitor of apoptosis protein, overexpressed in most human malignancies and implicated in mitosis regulation and preservation of cell viability. In order to investigate the prevalence and clinical significance of survivin in early-stage non-small cell lung carcinoma (NSCLC), survivin mRNA levels and protein expression were evaluated, using quantitative real-time RT-PCR and immunohistochemistry, respectively, in a series of 83 patients with stage I (IA and IB) surgically resected NSCLC. Detectable survivin mRNA levels could be demonstrated in all non-neoplastic lung tissue samples and in the tumours analysed. Survivin mRNA levels were elevated in 80 carcinomas (96%) compared to normal lung (p = 0.008). Among all tumours, survivin transcripts were present at a higher level in squamous cell carcinomas (p = 0.0022). Cytoplasmic and nuclear immunoreactivity was found in 70% and 80% of tumours, respectively and both were present in 54%. Cytoplasmic immunoreactivity correlated with tumour stage (p = 0.019). Survivin expression levels did not correlate with patient survival. In one specimen, cytoplasmic and focal nuclear immunostaining was observed in dysplastic bronchial squamous metaplasia. These results document that survivin overexpression is almost always present in early-stage NSCLC, suggesting that this protein may play a role in lung tumourigenesis. This ubiquitous expression makes survivin an appealing new target for novel therapies in lung cancer. In addition, this study also documents that survivin overexpression could be exploited for diagnostic purposes and that quantitative real-time RT-PCR can be a useful tool for evaluating survivin activation in NSCLC.
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PMID:Survivin gene expression in early-stage non-small cell lung cancer. 1289 98

To identify critical genes that mediate p53-induced growth arrest and apoptosis at a global level, we profiled a human lung carcinoma cell model in which cells undergo growth arrest and apoptosis in a p53 and DNA damage-dependent manner. Profiling of the Affymetrix human HG-U1333 GeneChip, covering the entire human transcriptome, revealed about 3, 000 unique genes either induced or repressed during p53-induced growth arrest or apoptosis, respectively. A total of 1, 057 genes, including many well-known p53 targets, responded to both conditions. A mini apoptotic protein database was generated from 3, 033 unique apoptosis responsive genes. Analysis of this database yielded 23 proteins with a pro-apoptotic BH3 domain and three with anti-apoptotic BIR2/BIR3 domains, including well-known p53 targets: Bax, Puma, Noxa and survivin. In addition, 14 mitochondrial proteins were identified that contain a pro-apoptotic AVPI-like motif, and 15 proteins were identified that contain a DAVPI-like domain with the potential of being cleaved by caspases during apoptosis to release the AVPI motif. Many of the genes we identified with these domains do contain p53-binding sites either in the promoter or in the first three introns, suggesting a high probability of being direct p53 targets. Pathway analysis revealed that p53 might control the Wnt pathway through transcriptional regulation of some of its components. Thus, global chip profiling coupled with bioinformatics analysis is a powerful tool in identification of genes critical for p53-induced apoptosis. Further characterization of these genes will lead to a better understanding of the mechanism of p53 action and p53 regulation of other signaling pathways. It will also provide novel cancer drug targets for further validation.
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PMID:Global genechip profiling to identify genes responsive to p53-induced growth arrest and apoptosis in human lung carcinoma cells. 1450 18

Malignant transformation of cells is accompanied by multiple genetic abnormalities with aberrant expression of genes. By using the reverse transcriptase polymerase chain reaction (RT-PCR) assay, we have assessed the regulation of survivin gene expression in a prospectively collected series of 83 human non small-cell lung cancers. Survivin gene transcripts were identified in 71 (85.5%) of the tumor samples, while they were detected in only 10 (12%) of the paired histopathologically normal lung samples. Furthermore, a diminished overall survival was associated with survivin expression (Log-rank, P=0.01). This review discusses the structure, expression, and function of the survivin gene. It presents updated pooled data on survivin, analyzed by either immunochemistry or by RT-PCR, and the clinical correlates of aberrant expression in several tumors. We conclude that estimation of survivin gene transcripts by RNA techniques may have relevant applications in the prognostic and therapeutic assessment of lung cancer.
Clin Lung Cancer 1999 Nov
PMID:The anti-apoptosis survivin gene and its role in human cancer: an overview. 1473 65

Survivin is expressed in most tumor cells and has been associated with both anti-apoptosis and mitotic progression. However, the mechanism of regulation of the survivin expression remains unclear. In this study we investigated the expression and regulation of survivin in the nitric oxide (NO)-exposed human lung carcinoma cells. The lung carcinoma cell lines CL3, H1299, and A549 but not normal lung fibroblast expressed high levels of survivin proteins. NO donors S-nitroso-N-acetyl-penicillamine (SNAP) and sodium nitroprusside (SNP) decreased the survivin expression. SNAP (0.4 mm, 24h)and SNP (1 mm, 24 h) significantly induced cytotoxicity and apoptosis in lung carcinoma cells. Furthermore, SNAP inhibited the cell growth and increased the fractions of G(2)/M phase. The levels of cyclin B1 and phospho-cdc2-(Thr-161) proteins were inhibited in the NO-exposed cells. The cdc25 phosphatase inhibitors (Cpd 5 and NSC 663284) and the cdc2 kinase inhibitors (alsterpaullone and purvalanol A) enhanced SNP-induced cytotoxicity and the decrease in survivin expression. However, overexpression of survivin by a pOTB7-survivin vector reduced SNP-induced cell growth inhibition and cytotoxicity. In addition, SNP activated the phosphorylation of p38 mitogen-activated protein (MAP) kinase. The specific p38 MAP kinase inhibitor, SB202190, significantly decreased the cytotoxicity and increased the survivin levels in NO donor-treated and inducible NOS-transfected cells. Conversely, anticancer agents including quercetin, arsenite, and cisplatin but not genistein increased the levels of survivin protein. Our results indicated for the first time that NO inhibited the expression of survivin, which was down-regulated by the p38 MAP kinase pathway.
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PMID:Down-regulation of survivin in nitric oxide-induced cell growth inhibition and apoptosis of the human lung carcinoma cells. 1498 4

Quercetin, a ubiquitous bioactive plant flavonoid, has been shown to inhibit the proliferation of cancer cells. However, the regulation of survivin and p53 on the quercetin-induced cell growth inhibition and apoptosis in cancer cells remains unclear. In this study, we investigated the roles of survivin and p53 in the quercetin-treated human lung carcinoma cells. Quercetin (20-80 mum for 24 h) induced the cytotoxicity and apoptosis in both A549 and H1299 lung carcinoma cells in a concentration-dependent manner. Additionally, quercetin inhibited the cell growth, increased the fractions of G(2)/M phase, and raised the levels of cyclin B1 and phospho-cdc2 (threonine 161) proteins. Moreover, quercetin induced abnormal chromosome segregation in H1299 cells. The survivin proteins were highly expressed in mitotic phase and were located on the midbody of cytokinesis; however, the survivin proteins were increased and concentrated on the nuclei following quercetin treatment in the lung carcinoma cells. Transfection of a survivin antisense oligodeoxynucleotide enhanced the quercetin-induced cell growth inhibition and cytotoxicity. Subsequently, quercetin increased the levels of total p53 (DO-1), phospho-p53 (serine 15), and p21 proteins, which were translocated to the nuclei in A549 cells. Treatment with a specific p53 inhibitor, pifithrin-alpha, or transfection of a p53 antisense oligodeoxynucleotide enhanced the cytotoxicity of the quercetin-treated cells. Furthermore, transfection of a small interfering RNA of p21 enhanced the quercetin-induced cell death in A549 cells. Together, our results suggest that survivin can reduce the cell growth inhibition and apoptosis, and p53 elevates the p21 level, which may attenuate the cell death in the quercetin-treated human lung carcinoma cells.
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PMID:Survivin and p53 modulate quercetin-induced cell growth inhibition and apoptosis in human lung carcinoma cells. 1545 84

It has been suggested that suppression of apoptosis may contribute to the development and progression of cancer. Anti-apoptotic survivin and livin genes are highly expressed in cancer cells and transformed cells, but show little or no expression in normal differentiated tissues. However, there are no available data concerning livin expression in non-small-cell lung cancer (NSCLC). We therefore measured livin mRNA and survivin mRNA expression in 38 NSCLC cancer samples and 15 paired non-cancerous lung tissue samples using a quantitative reverse transcription-polymerase chain reaction (RT-PCR). While both mRNAs showed higher expression in cancers than non-cancerous tissues (P < 0.001), livin mRNA and survivin mRNA expression did not correlate with one another. When a cut-off value for positivity was set at the mean + S.D. for expression values in non-cancerous tissues, positivity rates for livin mRNA and survivin mRNA expression were 76.3% (29 of 38) and 36.8% (14 of 38) in lung cancers and 6.7% (1 of 15) and 0% (0 of 15), respectively, in paired non-cancerous lung tissue samples. Livin mRNA and survivin mRNA expression in tumors were up-regulated in 23 of 31 (74.2%) early-stage NSCLC patients and 11 of 31 (35.5%), respectively. Expression of both mRNAs in tumors varied independently of tumor histology. These results support the possibility that the livin gene may play a role in NSCLC development and increased expression of livin mRNA may serve as a new target for lung cancer treatment as well as survivin.
Lung Cancer 2004 Dec
PMID:Expression of survivin mRNA and livin mRNA in non-small-cell lung cancer. 1554 14

A novel strategy achieved the eradication of lung tumor metastases by joint suppression of angiogenesis in the tumor neovasculature and induction of tumor cell apoptosis. This was accomplished by CTLs induced by a DNA vaccine encoding secretory chemokine CCL21 and the inhibitor of apoptosis protein survivin, overexpressed by both proliferating endothelial cells in the tumor vasculature and tumor cells. Oral delivery of this DNA vaccine by doubly attenuated Salmonella typhimurium (dam(-) and AroA(-)) to such secondary lymphoid organs as Peyer's patches in the small intestine, elicited marked activation of antigen-presenting dendritic cells, and an effective CD8(+)T cell immune response against the survivin self-antigen. This resulted in eradication or suppression of pulmonary metastases of non-small cell lung carcinoma in both prophylactic and therapeutic settings in C57BL/6J mice. Moreover, the suppression of angiogenesis induced by the vaccine did not impair wound healing or fertility of treated mice. It is anticipated that such novel DNA vaccines will aid in the rational design of future strategies for the prevention and treatment of cancer.
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PMID:A DNA vaccine targeting survivin combines apoptosis with suppression of angiogenesis in lung tumor eradication. 1569 99

Survivin and livin are highly expressed in cancer cells and transformed cells, but show little or no expression in normal differentiated tissues. Although human antibody responses to cancer-associated antigens have been detected, the response to livin has not yet been described in lung cancer patients. We examined prevalence of anti-livin antibodies in such patients with a specific enzyme-linked immunosorbent assay (ELISA) using recombinant protein. Using a cutoff value for positivity determined as the mean absorbance +2S.D. for healthy control samples, 19 of 37 lung cancer patients (51.3%) were positive for anti-livin antibodies. Of 31 samples from the same lung cancer patients, 18 (58.1%) were positive for anti-survivin antibodies. When sera from 31 lung cancer patients were assessed simultaneously by anti-survivin and anti-livin ELISAs. Twenty-one patients (71%) were positive for survivin, livin, or both. Intensity of anti-livin antibody responses did not correlate with intensity of anti-survivin responses. Like anti-survivin antibodies, anti-livin antibodies, thus, can be detected in many lung cancer patients. Testing for both antibodies together may prove useful in detecting lung cancer, but more extensive studies are needed to establish the clinical significance of anti-livin antibodies.
Lung Cancer 2005 May
PMID:Detection of autoantibodies to livin and survivin in Sera from lung cancer patients. 1582 21

Although it was observed that inhibition of the antiapoptotic protein survivin expression in lung cancer cells induces apoptosis, the expression and role of survivin variants (survivin-2B and survivin-DeltaEx3) in lung cancer have not yet been characterized. We analyzed 24 non-small-cell lung cancer (NSCLC) samples by semi-quantitative RT-PCR. Surprisingly, our results revealed that high-level expression of survivin-2B is significantly associated with the patient category of "no relapse and alive" (p-value<0.0001). In contrast, high-level expression of survivin-DeltaEx3 is highly associated with the patient category of "relapse and dead" (p-value<0.0001). Consistent with this observation, exogenous expression of survivin-2B in A549 lung cancer cells inhibited cell growth, disrupted the mitochondria potential, and induced apoptotic cell death, while expression of survivin-DeltaEx3 protected the mitochondria potential and facilitated cell survival. These findings provide evidence that survivin-2B and survivin-DeltaEx3 play opposite roles in disease relapse and NSCLC cell survival, which is likely through the differential modulation of mitochondrial potential. Thus, controlling the differential expression of survivin-2B and survivin-DeltaEx3 may represent novel approaches for cancer therapeutics in NSCLC.
Lung Cancer 2005 Sep
PMID:Differential expression of survivin-2B and survivin-DeltaEx3 is inversely associated with disease relapse and patient survival in non-small-cell lung cancer (NSCLC). 1593 46


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