Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08758 (annexin V)
 9,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several lines of evidence now indicate that type 1 insulin-like growth factor receptor (IGF1R) function may be particularly important in the pathogenesis of the pediatric cancer neuroblastoma. Modulating the expression of specific genes involved in neuroblastoma tumorigenesis could provide a much needed alternative treatment strategy for poor prognosis disease. We now report construction of an antisense expression vector to the IGF1R that markedly reduces cellular IGF1R levels and inhibits the proliferation and clonogenicity of neuroblastoma cells in vitro but not that of IGF1R null cells. This antitumor activity is associated with the induction of apoptotic cell death in transfected cells, as measured by annexin V staining and flow cytometry. Direct injection of this vector into established tumors growing in syngeneic mice results in a marked inhibition of tumor growth with complete and durable tumor regression in one-half of the animals. This effect appears to be immunologically mediated in that vector injection of neuroblastoma tumors growing in severe combined immunodeficiency mice results in only modest delay of tumor growth. Our results suggest that inhibition of IGF1R expression by direct intratumoral delivery of an antisense construct could provide a novel therapeutic approach in the management of poor prognosis neuroblastoma.
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PMID:Inhibition of insulin-like growth factor I receptor expression in neuroblastoma cells induces the regression of established tumors in mice. 985 76

Surfactant-associated protein A (SP-A) is a component of pulmonary surfactant that binds to a specific receptor (SPAR) on the surface of type II alveolar cells of the lung and regulates gene expression and surfactant secretion. Previously we have shown that activation of SPAR by SP-A binding initiates a signal through pathways that involve tyrosine phosphorylation, include IRS-1, and entail activation of phosphatidylinositol 3-kinase (PI3K). In other cell types, cytokines that activate the PI3K signaling pathway promote cell survival. Therefore we investigated whether there was an effect of SP-A on apoptosis as measured by DNA laddering, FACS analysis, TUNEL assay, and annexin V binding. SP-A protected primary cultures of rat type II alveolar cells against the apoptotic effects of etoposide and UV light and also protected the H441 human Clara lung tumor cell line against staurosporine-induced apoptosis. The protective effects of SP-A were abrogated by inhibition of either tyrosine-specific protein kinase activity or PI3K. SP-A/SPAR interaction thus initiates a signaling pathway that regulates apoptosis in type II cells. These findings may be important in understanding the pathogenesis of acute lung injury and pulmonary tumorigenesis and may suggest new therapeutic options.
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PMID:Natural protection from apoptosis by surfactant protein A in type II pneumocytes. 1116 17

Telomere stabilisation is a critical step in tumorigenesis and telomerase, an enzyme which counteracts telomeric DNA loss, is active in most tumours. Conflicting evidence has been published concerning the potential use of telomerase activity as a measurement of drug-induced tumour cell killing. In this study, the time courses of telomerase loss and induction of apoptosis were investigated in two testicular cell lines, Susa CP and 833 K, following 4-h exposure to cisplatin, melphalan or doxorubicin. Telomerase activity was only affected in both cell lines at 20 h following exposure to high concentrations of cisplatin (100x the drug concentrations causing 50% growth inhibition (IC(50) values)). The time course of melphalan-induced telomerase loss, which was again only apparent at 100x IC(50) concentrations, varied between the cell lines and doxorubicin (100x IC(50)) did not induce telomerase loss in either of the cell lines. Importantly, the levels and rates of appearance of apoptotic cells (nuclear morphology and annexin V staining) were similar for all three drugs in both cell lines; i.e. cisplatin, melphalan and doxorubicin (100x IC(50)) caused similar frequencies of apoptosis in Susa CP cells at 24 h whereas telomerase activities were 65, 123 and 96% of the control, respectively. The possibility that telomerase activity was lost following cisplatin treatment through a direct interaction of cisplatin with telomerase was discounted. Additionally, the relative levels of the RNA component of telomerase (hTR) and mRNA for the telomerase catalytic subunit (hTERT) were not related to the observed decreases in telomerase activity. These data indicate that telomerase activity is not a reliable indicator of chemosensitivity in human testicular cancer cells. Furthermore, cisplatin-induced loss of telomerase activity is not due to a direct reaction with the enzyme or decreased hTR levels.
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PMID:Decreased telomerase activity is not a reliable indicator of chemosensitivity in testicular cancer cell lines. 1187 54

Squamous cell carcinoma (SCC) is the end product of a multistep process characterized by a progression from normal epithelial cells through metaplastic or dysplastic intraepithelial changes that evolve into invasive cancer. Since retinamides have shown promising in vivo anti-tumoral activity, we studied effects and effector mechanisms of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) on squamous cells at progressing stages of tumorigenesis. To this end, an in vitro model of squamous carcinogenesis consisting of normal human keratinocytes, human papilloma virus (HPV)-immortalized keratinocytes (UP) and tumorigenic HPV-immortalized/v-Ha-ras transfected keratinocytes (UPR) was used. 4-HPR treatment affected cell growth at doses higher than 1.5 microM. Flow cytometric measurements of DNA content and annexin V revealed that cell growth decrease was mainly due to apoptosis at 4-HPR concentrations of or below 15 microM, and necrosis at higher concentrations. The effects were similar in the three cell types of the in vitro model, as well as in three SCC cell lines, suggesting that sensitivity to 4-HPR is independent of the degree of squamous cell tumorigenesis in the in vitro model. We further investigated whether mitochondrial damage was involved in the course of 4-HPR-induced apoptosis. Treatment of squamous cells with the antioxidant L-ascorbic acid inhibited apoptosis, indicating that 4-HPR increases production of free radicals. Measures of mitochondrial membrane potentials showed that 4-HPR induced membrane permeability transition (MPT), and that MPT-inhibitors were able to reduce apoptosis. This indicates that MPT is involved in apoptosis signalling by 4-HPR. Finally, we studied the role of caspases. We found that caspases 8, 9 and 3 participate in 4-HPR-mediated apoptosis of squamous cells, and that MPT is an upstream event that regulates caspase activity. Caspase 8 was activated independently of the Fas-Fas ligand pathway.
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PMID:Apoptosis of squamous cells at different stages of carcinogenesis following 4-HPR treatment. 1189 59

Apoptosis, a genetically encoded process of cellular suicide, comprises an intrinsic cellular defence against tumorigenesis. bak(for bcl-2 homologous antagonist/killer) is a new apoptosis-inducing gene found recently, which is identified in all tissues examined. Initial work of Farrow, Chittenden and Klefer indicated that bak plays an important role in apoptosis. Successive work of others suggests inactivity of Bak always accompanies the development of tumor cells. In this work, a shuttle vector harboring bak gene, pCA13-bak, was constructed and used to cotransfect into the cell line 293 together with a recombinant plasmid, pBHG11, containing most of adenovirus genome. A mutant adenovirus(delete E1, E3 region)carring bak, Ad-bak, was obtained, and purified. Dot blot identified the construction of recombinant virus was successful. HeLa cells were infected by this virus. Some manners were used to identify the changes of HeLa cells including Annexin V-FITC staining which made the reversed PS observed directly, microscope observation and others. The characteristic morphology of apoptotic cells was due to Ad-bak. The experiment suggests that bak is a strong apoptosis-inducing gene, and a potential gene which could be used in gene therapy on tumor.
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PMID:Induction of Apoptosis in Tumor Cells by a Recombinant Adenovirus with bak Gene. 1207 28

Head and neck cancer is a frequent malignancy with a complex, and up to now not clear etiology. Therefore, despite of improvements in diagnosis and therapy, the survival rate with head and neck squamous-cell carcinomas is poor. For a better understanding of the molecular mechanisms behind the process of tumorigenesis and tumor progression, we have analyzed changes of protein expression between microdissected normal pharyngeal epithelium and tumor tissue by ProteinChip technology. For this, cryostat sections from head and neck tumors (n = 57) and adjacent mucosa (n = 44) were laser-microdissected and analyzed on ProteinChip arrays. The derived mass spectrometry profiles exhibited numerous statistical differences. One peak significantly higher expressed in the tumor (p = 0.000029) was isolated by two-dimensional gel electrophoresis and identified as annexin V by in-gel proteolytic digestion, peptide mapping, tandem mass spectrometry analysis, and immuno-deplete assay. The relevance of this single marker protein was further evaluated by immunohistochemistry. Annexin-positive tissue areas were re-analyzed on ProteinChip arrays to confirm the identity of this protein. In this study, we could show that biomarker in head and neck cancer can be found, identified, and assessed by combination of ProteinChip technology, two-dimensional gel electrophoresis, and immunohistochemistry. In our experience, however, such studies only make sense if a relatively pure microdissected tumor tissue is used. Only then minute changes in protein expression between normal pharyngeal epithelium and tumor tissue can be detected, and it will become possible to educe a tumor-associated protein pattern that might be used as a marker for tumorigenesis and progression.
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PMID:Biomarker discovery and identification in laser microdissected head and neck squamous cell carcinoma with ProteinChip technology, two-dimensional gel electrophoresis, tandem mass spectrometry, and immunohistochemistry. 1282 40

Glycogen synthase kinase (GSK)-3beta is a constitutively active, proline-directed serine/threonine kinase that controls growth modulation and tumorigenesis through multiple intracellular signaling pathways. How GSK-3beta regulates signaling pathways induced by cytokines such as tumor necrosis factor (TNF) is poorly understood. In this study, we used fibroblasts derived from GSK-3beta gene-deleted mice to understand the role of this kinase in TNF signaling. TNF induced NF-kappaB activation as measured by DNA binding in wild-type mouse embryonic fibroblasts, but deletion of GSK-3beta abolished this activation. This inhibition was due to suppression of IkappaBalpha kinase activation and IkappaBalpha phosphorylation, ubiquitination, and degradation. TNF-induced NF-kappaB reporter gene transcription was also suppressed in GSK-3beta gene-deleted cells. NF-kappaB activation induced by lipopolysaccharide, interleukin-1beta, or cigarette smoke condensate was completely suppressed in GSK-3beta(-/-) cells. Deletion of GSK-3beta also abolished TNF-induced c-Jun N-terminal kinase and p44/p42 mitogen-activated kinase activation. Most surprisingly, TNF-induced Akt activation also required the presence of GSK-3beta. TNF induced expression of the NF-kappaB-regulated gene products cyclin D1, COX-2, MMP-9, survivin, IAP 1, IAP 2, Bcl-x(L), Bfl-1/A1, TRAF1, and FLIP in wild-type mouse embryonic fibroblasts but not in GSK-3beta(-/-) cells, and this correlated with potentiation of TNF-induced apoptosis as indicated by cell viability, annexin V staining, and caspase activation. Overall, our results indicate that GSK-3beta plays a critical role in TNF signaling and in the signaling of other inflammatory stimuli and that its suppression can be exploited as a potential target to inhibit angiogenesis, proliferation, and survival of tumor cells.
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PMID:Genetic deletion of glycogen synthase kinase-3beta abrogates activation of IkappaBalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor. 1525 41

Bilirubin is the principal end product of heme degradation. Prompted by epidemiologic analyses demonstrating an inverse correlation between serum bilirubin levels and cancer mortality, we examined the effect(s) of bilirubin on the growth and survival of colon adenocarcinoma cells. Adenocarcinoma cell monolayers were treated with bilirubin over a range of bilirubin:BSA molar ratios (0-0.6), and viability was assessed colorimetrically. Apoptosis was characterized by TUNEL assay, annexin V staining and caspase-3 activation. The mechanism(s) by which bilirubin induces apoptosis was investigated by Western blotting for cytochrome c release, assaying for caspase-8 and caspase-9 activation and for mitochondrial depolarization by JC-1 staining. The direct effect of bilirubin on the membrane potential of isolated mitochondria was evaluated using light-scattering and fluorescence techniques. Bilirubin decreased the viability of all colon cancer cell lines tested in a dose-dependent manner. Cells exhibited substantial apoptosis when exposed to bilirubin concentrations ranging 0-50 microM, as demonstrated by an 8- to 10-fold increase in TUNEL and annexin V staining and in caspase-3 activity. Bilirubin treatment evokes specific activation of caspase-9, enhances cytochrome c release into the cytoplasm and triggers the mitochondrial permeability transition in colon cancer monolayers. Additionally, bilirubin directly induces the depolarization of isolated rat liver mitochondria, an effect that is not inhibited by cyclosporin A. Bilirubin stimulates apoptosis of colon adenocarcinoma cells in vitro through activation of the mitochondrial pathway, apparently by directly dissipating mitochondrial membrane potential. As this effect is triggered at concentrations normally present in the intestinal lumen, we postulate a physiologic role for bilirubin in modulating colon tumorigenesis.
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PMID:Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization. 1538 69

In primary glioblastomas and other tumor types, the epidermal growth factor receptor (EGFR) is frequently observed with alterations, such as amplification, structural rearrangements, or overexpression of the gene, suggesting an important role in glial tumorigenesis and progression. In this study, we investigated whether posttranscriptional gene silencing by vector-mediated RNAi to inhibit EGFR expression can reduce the growth of cultured human gli36 glioma cells. To "knock down" EGFR expression, we have created HSV-1-based amplicons that contain the RNA polymerase III-dependent H1 promoter to express double-stranded hairpin RNA directed against EGFR at two different locations (pHSVsiEGFR I and pHSVsiEGFR II). We demonstrate that both pHSVsiEGFR I and pHSVsiEGFR II mediated knock-down of transiently transfected full-length EGFR or endogenous EGFR in a dose-dependent manner. The knock-down of EGFR resulted in the growth inhibition of human glioblastoma (gli36-luc) cells both in culture and in athymic mice in vivo. Cell cycle analysis and annexin V staining revealed that siRNA-mediated suppression of EGFR induced apoptosis. Overall HSV-1 amplicons can mediate efficient and specific posttranscriptional gene silencing.
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PMID:Herpes simplex virus 1 amplicon vector-mediated siRNA targeting epidermal growth factor receptor inhibits growth of human glioma cells in vivo. 1611 10

To determine if A1 adenosine receptors mediate breast tumorigenesis, we evaluated A1 receptor expression in human tumor cell lines and human primary breast tumor tissues using both quantitative RT-PCR and Western blot analysis. A1 receptor mRNA expression is upregulated in all breast tumor cell lines examined (n=7) compared to normal mammary epithelial cells/cell lines (n=3) as determined by quantitative RT-PCR analysis. Western blot analysis indicates that protein expression of A1 adenosine receptor is higher in 15 (62.5%) of 24 human primary breast tumor tissues than in matched normal breast tissue. To explore its cellular function, the A1 adenosine receptor was depleted by small interfering RNA (siRNA) in MDA-MB-468 human breast tumor cells. Depletion of A1 receptors in MDA-MB-468 breast tumor cells attenuated both cell growth and cell proliferation as measured by cell number counts and [(14)C]-thymidine incorporation, respectively. Cell cycle analysis indicated that depletion of A1 receptors by siRNA impairs G(1) checkpoint, leading to marked accumulation of cells in G(2)/M phase, in agreement with the inhibitory effect on cell proliferation. Further supporting this finding, synchronization studies of Hela cells in various cell cycle phases suggest that A1 receptor expression is suppressed in G(2)/M cells and depletion of A1 receptor expression by siRNA produced differential expression of several key cell cycle regulators, i.e., accumulation of the cyclin-dependent kinase inhibitor p27 with concomitant reduction of CDK4 and cyclin E proteins. In addition to the impact on cell cycle progression, depletion of A1 receptors by siRNA results in substantial cell death and apoptosis as determined by FACS analysis and annexin V staining method. Together these findings suggest that the A1 adenosine receptor may contribute to tumor cell growth and survival in breast tumor cells.
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PMID:RNA interference targeting of A1 receptor-overexpressing breast carcinoma cells leads to diminished rates of cell proliferation and induction of apoptosis. 1629 23


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