Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It was recently reported that the human CD109 gene encodes a glycosyl-phosphatidylinositol-anchored glycoprotein that is a member of the alpha(2)-macroglobulin/C3, C4, C5 family of thioester-containing proteins. In this study, we found that the expression of mouse CD109 gene was upregulated in NIH3T3 cells expressing RET tyrosine kinase with a multiple endocrine neoplasia 2B mutation. Northern blot analysis showed a high level of expression of the CD109 gene only in the testis in normal human and mouse tissues. In addition, its expression was high in some human tumor cell lines, which included squamous cell carcinoma and glioblastoma cell lines, whereas it was undetectable in neuroblastoma and small-cell lung carcinoma cell lines. When CD109 expression was examined in 33 cases of human lung cell carcinomas by quantitative RT-PCR, a significant high expression of CD109 was detected in about half of squamous cell carcinomas examined, but not in adenocarcinoma, large-cell carcinoma and small-cell carcinoma. Similarly, upregulation of CD109 was observed in nine out of 17 esophageal squamous cell carcinomas. Thus, these results suggested that CD109 might be a useful molecular target for the development of new therapeutics for malignant tumors, such as squamous cell carcinoma.
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PMID:Expression of CD109 in human cancer. 1511 2

The expression of the prion (PRNP) and prion like-doppel (PRND) genes and the presence of the proteins prion (PrP) and doppel (Dpl) were investigated in human gliomas. The PRNP and PRND expression profiles were evaluated by real-time reverse transcription-quantitative PCR in low- and high-grade astrocytomas, in glioblastoma-derived cell lines and in non-glial tumor specimens. The presence of PrP and Dpl proteins and their cellular localization were evaluated by Western blot and immunohistochemistry. High levels of PRNP expression were found in all tumoral samples studied. Unlike the non-tumoral controls, PRND was aberrantly expressed in glioblastoma multiforme and in two glioblastoma multiforme-derived cell lines, even in the absence of the PRND gene amplification. PRND expression was directly related to malignancy of the tumor: highest in glioblastoma multiforme, lower in anaplastic astrocytoma and even lower in the low-grade astrocytoma samples. High levels of PRND were also found in non-glial malignant tumor samples, such as gastric adenocarcinoma and anaplastic meningioma. Western blot analysis confirmed the PrP and Dpl expression, displaying variability in the electrophoretic patterns. Immunohistochemical analysis revealed a diffuse cytoplasmatic Dpl distribution in different astrocytic neoplastic cells, in infiltrating lymphocytes and in blood vessel endothelial cells. Of note, Dpl reactivity was different from that of the PrP, since PrP showed typical Golgi and membrane localised staining. Our findings suggest that the PRND gene might be a useful molecular marker in astrocytoma progression and in tumor grade definition. Understanding of the mechanisms of PRND increased expression might provide insight into the regulatory pathways of glioma development.
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PMID:Differential expression of the prion-like protein doppel gene (PRND) in astrocytomas: a new molecular marker potentially involved in tumor progression. 1527 17

Abeta peptides are naturally occurring peptides forming beta-sheet aggregates that constitute an integral component of senile plaques and vascular deposits in Alzheimer's disease. Since several peptides adopting a beta-sheet conformation have been shown to be anti-angiogenic, we investigated the effect of Abeta on angiogenesis. We show that in vitro, Abeta dose-dependently inhibits the formation of capillaries by human brain endothelial cells plated on Matrigel and stimulates capillary degeneration at high doses. Preparations of Abeta peptides containing a higher content of beta-sheet structures are more potently anti-angiogenic in vitro. Ex vivo, Abeta dose-dependently opposes angiogenesis in rat aortae and in human middle cerebral arteries. In vivo, Abeta dose dependently inhibits angiogenesis in the chick chorioallantoic membrane assay and suppresses bFGF-induced blood vessel formation in the corneal micropocket and Matrigel plug assays. Since angiogenesis is required for tumor growth, we explored the effect of Abeta on human glioblastoma (U87MG) and human lung adenocarcinoma (A549) tumors. We show that intra-tumoral injection of Abeta potently inhibits the growth and vascularization of human glioblastoma and human lung adenocarcinoma tumor xenografts in nude mice. Similarly to the intra-tumoral injection regimen, Abeta delivered intraperitoneally also suppressed the growth of human lung adenocarcinoma tumor xenografts. Altogether our data show that Abeta is an angiogenesis inhibitor.
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PMID:Inhibition of angiogenesis by Abeta peptides. 1530 99

5-Aminolevulinic acid (ALA), a precursor of the endogenous photosensitizer protoporphyrin IX, is used in the photodynamic therapy (PDT) of cancer. Sub-lethal ALA-PDT (1-min irradiation with 370-450 nm blue light, 0.6 mW/cm(2) after 2-h incubation with 1 mM ALA) has been earlier shown to change cell morphology and to inhibit both trypsin-induced detachment of cultured cancer cells from the plastic substrata and cell attachment to the bottom of the plastic well plates. In the present study, we found that such treatment of human adenocarcinoma WiDr cells grown in dense colonies stimulated the formation of actin cortex between cells in the colonies and increased the number of actin stress fibres in some, but not in all, cells. However, ALA-PDT did not change the microtubular cytoskeleton in these cells. A similar treatment of glioblastoma D54Mg cells, which grow separately and communicate by protrusions, caused loss of fibrillar actin structures in growth cones, retraction of protrusions, and surface blebbing in some cells. The application of the cytoskeleton inhibitors cytochalasin D, colchicine or taxol showed that the inhibition of trypsin-induced detachment of photosensitized WiDr cells was related to ALA-PDT-induced changes in actin and microtubular cytoskeleton. Some signal transduction processes are suggested to be involved in ALA-PDT-induced changes in cytoskeleton, cell shape, and adhesion.
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PMID:The effect of sub-lethal ALA-PDT on the cytoskeleton and adhesion of cultured human cancer cells. 1571 35

Myc is a ubiquitous mediator of cell proliferation that transactivates the expression of various genes through E-box sites. Here we report a novel gene, mimitin (Myc-induced mitochondrial protein), that encodes a mitochondrial protein with a molecular mass of 20 kDa. We demonstrated that the transcription of mimitin is directly stimulated by c-Myc. To investigate the role of Mimitin, its expression was suppressed by the RNA interference (RNAi) technique. Whereas specific inhibition of mimitin expression did not affect cell proliferation in human cervical carcinoma, colon adenocarcinoma, and hepatocarcinoma cell lines, it did suppress cell proliferation in human glioblastoma, esophageal squamous cell carcinoma (ESCC), and embryonic lung fibroblastic cells, with the greatest suppression efficiency in ESCC cells. To investigate whether mimitin is related to tumorigenesis in ESCC in vivo, the expression of Mimitin protein in ESCC tissues was studied. Mimitin was highly expressed in 80% (28 of 35) of ESCC tumors, suggesting that high expression of Mimitin is a characteristic feature of ESCC. The expression level of Mimitin was found to be correlated with that of c-Myc and cell proliferation, but not with the histopathological grade, stage of cancer, or age of patients. Taken together, these results suggest that the novel gene mimitin is a direct transcriptional target of c-Myc, and is involved in Myc-dependent cell proliferation at least in ESCC cells.
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PMID:A novel Myc-target gene, mimitin, that is involved in cell proliferation of esophageal squamous cell carcinoma. 1577 66

The purpose of this study was to examine whether the dietary components n-6 and n-3 polyunsaturated fatty acids (PUFAs) may potentiate the effect of photodynamic therapy (PDT) in human cancer cell lines by enhancing the lipid peroxidation. The effects of the porphyrin precursor 5-aminolevulinic acid (5-ALA) and light (320 < lambda < 440 nm, 33 W m(-2)), with or without docosahexaenoic acid (DHA) or arachidonic acid (AA), were tested in the colon carcinoma cell lines SW480 and WiDr, the glioblastoma cell line A-172 and the lung adenocarcinoma cell line A-427. The production of endogenous protoporphyrin IX (PpIX) varied substantially between the cell lines and was approximately 4-fold higher in WiDr as compared with SW480. Cell killing by 5-ALA-PDT also varied between the cell lines, but without clear correlation with PpIX levels. Treatment with DHA or AA (10 or 70 microM, 48 or 72 h) in combination with 5-ALA-PDT (1 or 2 mM) enhanced the cytotoxic effect in A-172 and A-427 cells, but not in SW480 and WiDr cells. While 5-ALA-PDT alone increased the lipid peroxidation in A-172 and WiDr cells only, 5-ALA-PDT plus PUFAs increased the lipid peroxidation substantially in all four cell lines. Interestingly, alpha-tocopherol (50 microM, 48 h) strongly reduced lipid peroxidation after all treatments in all cell lines, while cytotoxicity was only reduced substantially in A-427 cells. This demonstrates that induction of lipid peroxidation is not a general mechanism responsible for the cytotoxicity of 5-ALA-PDT, although it may be important in cell lines with an inherent sensitivity to lipid peroxidation products. Thus, the mechanisms of cell growth inhibition/cell killing by PDT are complex and cell specific.
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PMID:Cell specific effects of polyunsaturated fatty acids on 5-aminolevulinic acid based photosensitization. 1580 9

Combining gene therapy with radiotherapy and chemotherapy holds potential to increase the efficacy of cancer treatment, while minimizing side effects. We tested the responsiveness of synthetic gene promoters containing CArG elements from the Early Growth Response 1 (Egr1) gene after neutron irradiation, doxorubicin and cisplatin. Human MCF-7 breast adenocarcinoma and U373-MG glioblastoma cells were transfected with plasmids containing CArG promoters controlling the expression of the green fluorescent protein (GFP). Exposing the cells to neutrons, doxorubicin or cisplatin resulted in a significant induction of transgene expression. Therapeutic advantage was demonstrated by replacing the reporter with the herpes simplex virus thymidine kinase (HSVtk), able to convert the prodrug ganciclovir (GCV) into a cytotoxin. A 1.3 Gy neutron dose caused 49% growth inhibition in MCF-7 cells, which increased to 63% in irradiated CArG-HSVtk-transfectants treated with GCV. Exposure to 0.5 microM cisplatin or 0.01 microM doxorubicin induced a growth inhibition of 25-30% in MCF-7 cells. In the presence of GCV, this value increased to 65-70% in cells transfected with the CArG promoter constructs driving the expression of HSVtk. These data indicate that combining CArG-mediated HSVtk/GCV suicide gene therapy with radio- and chemotherapy can enhance antitumor toxicity, and validates future in vivo investigations.
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PMID:Gene therapy vectors containing CArG elements from the Egr1 gene are activated by neutron irradiation, cisplatin and doxorubicin. 1581 81

The involvement of beta-secretase and gamma-secretase in producing the beta-amyloid component of senile plaques found in the brain of Alzheimer's patients has fueled a major research effort to design selective inhibitors of these proteases. Interestingly, gamma-secretase cleaves several proteins including Notch, E-cadherin, CD44 and ErbB-4 (erythroblastic leukemia viral oncogene homolog 4), which are important modulators of angiogenesis. The beta-amyloid precursor protein, which is cleaved by beta-secretase and gamma-secretase to produce beta-amyloid, is highly expressed in the endothelium of neoforming vessels suggesting that it might play a role during angiogenesis. These data prompted us to explore the effects of beta and gamma-secretase inhibitors of different structures on angiogenesis and tumor growth. Both the gamma and beta-secretase inhibitors tested reduce endothelial cell proliferation without inducing cellular toxicity, suppress the formation of capillary structures in vitro and oppose the sprouting of microvessel outgrowths in the rat aortic ring model of angiogenesis. Moreover, they potently inhibit the growth and vascularization of human glioblastoma and human lung adenocarcinoma tumors xenotransplanted into nude mice. Altogether these data suggest that the gamma and beta-secretases play an essential role during angiogenesis and that inhibitors of the beta and gamma-secretases may constitute new classes of anti-angiogenic and anti-tumoral compounds.
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PMID:Inhibition of angiogenesis and tumor growth by beta and gamma-secretase inhibitors. 1587 19

Using "one-bead one-compound" combinatorial chemistry technology, we generated random peptide libraries containing millions of 90 mum TentaGel beads, each with its own unique amino acid sequence. A cyclic random 8-mer library was screened with CAOV-3 (a human ovarian adenocarcinoma cell line) and beads with a unique ligand that bind to the cell surface receptors were coated by one or more layers of cells. These positive beads were isolated, stripped, and microsequenced. Several peptide motifs were identified from these screenings, some of which were novel and unique, e.g., cDGX(4)GX(6)X(7)c. Structure-activity relationship studies of this peptide revealed that the l-aspartate residue at position 2, the two glycines at positions 3 and 5, and the two d-cysteines at the amino and COOH terminus are critical for activity. In addition, a hydrophobic residue was preferred at position X(4), whereas amino acids at positions X(6) and X(7) were more variable. Binding of this peptide to a number of different cancer cell lines and normal cells was also determined and we observed that peptides with this motif bound preferentially to three other human ovarian cancer cell lines (ES-2, SKOV-3, and OVCAR-3) as well as a human glioblastoma cancer cell line (A172). Structural analysis of the peptides using high-resolution nuclear magnetic resonance spectroscopy revealed strong conformational similarity among all peptides with cX(1)GX(4)GX(6)X(7)c motif. Blocking study with a panel of anti-integrin antibodies strongly suggests alpha3 integrin present on these ovarian adenocarcinoma cells is the target receptor for this peptide.
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PMID:Identification of novel targeting peptides for human ovarian cancer cells using "one-bead one-compound" combinatorial libraries. 1589 45

Hec1 (highly expressed in cancer) plays an important role in chromosome segregation by interacting with a subset of checkpoint proteins that survey proper chromosome alignment and bipolar spindle attachment. In order to disrupt mitotic progression of tumor cell lines, we have used retrovirus and adenovirus vectors that inhibit Hec1 synthesis. Vector-expressed short hairpin RNAs (shRNAs) caused very efficient depletion of the target protein, cellular arrest and considerable mitotic catastrophe induction 96 h post infection in human cervix-adenocarcinoma (HeLa) and glioblastoma (U-373-MG) cell lines. Furthermore, adenocarcinomas induced in the flanks of nude mice show significant reduction in size compared with control when treated with either Hec1-shRNA retroviruses or adenoviruses. These results indicate that depletion of Hec1 could be used as a new strategy to block the dividing cell, and therefore against cancer.
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PMID:RNA interference against Hec1 inhibits tumor growth in vivo. 1612 Dec 6


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