Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the regulatory mechanism of cell adhesion, we have searched for cellular inhibitory factors which prevent cell adhesion. The brain cytosol was found to inhibit the adhesion of various transformed cells to the substratum. An inhibitory 120-kDa protein was purified by sequential column chromatography. Peptide sequencing revealed that the protein is identical to amphiphysin1. GST-amphiphysin1 suppressed the attachment of HeLa cells to the plate when cells were cultured in the serum-containing medium. Vitronectin, a major cell-adhesive protein in serum and a ligand to alpha(v)beta3 integrin, was responsible for this cell attachment, and the vitronectin action was blocked by GST-amphiphysin1. GST-amphiphysin1 also inhibited the vitronectin-mediated spreading and migration of malignant melanoma cells. Furthermore, GST-amphiphysin1 bound directly to vitronectin. These findings point to the interesting possibility that amphiphysin1 could be a useful tool to inhibit cell-adhesive vitronectin.
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PMID:Amphiphysin1 inhibits vitronectin-mediated cell adhesion, spreading, and migration in vitro. 1256 47

Malignant gliomas are extremely aggressive cancers currently lacking effective treatment modalities. Gene therapy represents a promising approach for this disease. A requisite component for improving gene-based therapies of brain cancer includes tumor suppressor genes that exhibit cancer constrained inhibitory activity. Subtraction hybridization identified melanoma differentiation associated gene-7 (mda-7) as a gene associated with melanoma cell growth, differentiation and progression. Ectopic expression of mda-7 by means of a replication-incompetent adenovirus (Ad), Ad.mda-7, induces growth suppression and apoptosis selectively in diverse human cancers, without producing any apparent harmful effect in normal cells. We presently demonstrate that Ad.mda-7 induces growth inhibition and apoptosis in malignant human gliomas expressing both mutant and wild-type p53, and these effects correlate with an elevation in expression of members of the growth arrest and DNA damage (GADD) gene family. In contrast, infection with a recombinant Ad expressing wild-type p53, Ad.wtp53, specifically affects mutant p53 expressing gliomas. When tested in early passage normal and immortal human fetal astrocytes, growth inhibition resulting from infection with Ad.mda-7 or Ad.wtp53 is significantly less than in malignant gliomas and no toxicity is evident in these normal cells. Moreover, infection of gliomas with Ad.mda-7 or treatment with purified GST-MDA-7 protein sensitizes both wild-type and mutant p53 expressing tumor cells to the growth inhibitory and antisurvival effects of ionizing radiation, and this response correlates with increased expression of specific members of the GADD gene family. Since heterogeneity in p53 expression is common in evolving gliomas, the present findings suggest that Ad.mda-7 may, in many instances, prove more beneficial for the gene-based therapy of malignant gliomas than administration of wild-type p53.
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PMID:Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces growth suppression, apoptosis and radiosensitization in malignant gliomas in a p53-independent manner. 1260 43

The aberrant methylation of the CpG island promoter regions acquired by tumor cells is one mechanism for loss of gene function. The high methylation rate for RB1 and death-associated protein-kinase gene (DAP-kinase) (60 and 90%, respectively) previously found in brain metastases suggests this mechanism could be non-randomly associated to tumor progression and metastasis. Thus, in addition to these two genes, we determined the methylation status of the genes p16INK4a, glutathione S-transferase P1 (GSTP1), O6-methylguanine DNA methyltransferase (MGMT), thrombospondin-1 (THBS1), p14ARF, TP53, p73, and tissue inhibitor of metalloproteinase 3 (TIMP-3), in 18 brain metastases of solid tumors, with methylation specific PCR. The metastases were derived from malignant melanoma (three cases), lung carcinoma (six cases), breast carcinoma (three cases), ovarian carcinoma (two cases) and one each from colon, kidney, bladder and undifferentiated carcinoma. We detected methylation levels in the tumor samples of 83% in p16INK4a, 72% in DAP-kinase, 56% in THBS1, 50% in RB1, 39% in MGMT, 33% in GSTP1 and p14ARF each, 22% in p73 and TIMP-3 each, and 11% in TP53. The methylation index (number of genes methylated/number of genes tested) varied between 0.1 and 0.6, with an average of 0.42, indicating that a high grade of gene methylation accumulates parallel to the tumor metastasis process. Our data suggest an important role for gene methylation in the development of brain metastases, primarily involving epigenetic silencing of DAP-kinase, THBS1 and the cell-cycle regulators RB1/p16INK4a.
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PMID:Promoter methylation status of multiple genes in brain metastases of solid tumors. 1465 77

Previous studies have shown that glutathione S-transferases (GSTs) can operate in synergy with efflux transporters, multi-drug resistance proteins (MRPs), to confer resistance to several carcinogens, mutagens and anticancer drugs. To address the poorly documented role of the GSTM1 in cancer chemoresistance, we used CAL1 human melanoma cells expressing no endogenous GSTM1 and a high level of MRP1. Cells were transfected with an expression vector containing the GSTM1 cDNA, and different clones were selected expressing different levels of GSTM1 (RT-PCR, Western blot, and enzyme activity). Cells overexpressing GSTM1 displayed a 3- to 4-fold increase in resistance to anticancer drugs vincristine (VCR) and chlorambucil (CHB) in proliferation, cytotoxic, and clonogenic survival assays. Inhibitors of MRP1 (sulfinpyrazone, verapamil) and GST (dicumarol, curcumin) completely reversed the GSTM1-associated resistance to VCR, indicating that a MRP efflux function is necessary to potentiate GSTM1-mediated resistance to VCR. Conversely, MRP1 inhibitors had no effect on the sensitivity to CHB. Using immunofluorescence assay, GSTM1 was also shown to protect microtubule network integrity from VCR-induced inhibition of microtubule polymerization. In conclusion, these results show that GSTM1 alone is involved in melanoma resistance to CHB, whereas it can act in synergy with MRP1 to protect cells from toxic effects of VCR.
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PMID:Glutathione S-transferase M1 and multidrug resistance protein 1 act in synergy to protect melanoma cells from vincristine effects. 1504 19

The human mda-7/IL-24 gene product is normally expressed in melanocytes and certain lymphocyte populations. Loss of expression, a distinctive feature of many tumor suppressor genes, has been documented at RNA and protein levels in association with melanoma progression both in vitro as well as in human tumor-derived material. The MDA-7/IL-24 protein undergoes post-translational processing, including removal of an amino-terminal 48-residue signal peptide and extensive glycosylation prior to its secretion by producing cells. Its inherent cytokine properties have been documented in multiple reports, which have identified and characterized its cognate receptors and activation of the JAK/STAT signaling pathway following ligand/receptor docking. A notable and incompletely understood property of MDA-7/IL-24 is its ability to induce apoptosis in transformed cells, while having marginal growth suppressive effects on normal primary or immortalized cell lines. MDA-7/IL-24 has been delivered to cells, tumor xenografts and patients in clinical trials via a nonreplicating adenovirus (Ad.mda-7). Studies utilizing eukaryotically expressed and purified MDA-7/IL-24 protein from several sources have recapitulated some of the molecule's reported properties including receptor binding and JAK/STAT activation. Here, we report the properties and characteristics of a bacterially expressed and purified GST-MDA-7 fusion protein. These studies reveal that GST-MDA-7 retains its cancer-selective apoptosis-inducing properties, thereby providing a new reagent that will assist in defining the mechanism of action of this novel cytokine. In addition, retention of tumor-specific activity of GST-MDA-7 suggests that this protein may also have therapeutic applications.
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PMID:Mechanistic aspects of mda-7/IL-24 cancer cell selectivity analysed via a bacterial fusion protein. 1533 67

One important application of DNA microarray technology is the simultaneous analysis of gene expression of different mRNAs. Comparison of mRNA patterns of diseased and healthy tissue may help to understand the pathogenesis of a given disorder. In cancer tissue, identified dysregulated genes may serve as new molecular markers for diagnosis or prognosis or may ideally serve as new targets for therapy. Using membrane cDNA array technology, we analyzed gene expression in human melanomas, one of the most aggressive types of cancer with a high metastatic potential and with markedly increased incidence worldwide. To account for the heterogeneity of tumors, we compared total RNA from cutaneous melanoma metastases of 10 different patients with primary human melanocytes. An abundance of genes was dysregulated (up-/downregulated), which involved for example the apoptosis gene growth factor receptor-bound protein 10, Bcl2-associated X membrane protein, Bcl2 antagonist of cell death, glutathione S-transferase theta(1) and glutathione reductase. Ultimately, the identification of melanoma-associated genes may provide a potential therapeutic strategy for identifying and targeting malignant melanoma.
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PMID:Rapid identification of dysregulated genes in cutaneous malignant melanoma metastases using cDNA technology. 1538 85

Azurin is a member of a group of copper-containing redox proteins called cupredoxins. Different cupredoxins are produced by different aerobic bacteria as agents of electron transfer. Recently, we demonstrated that azurin enters into J774 and several types of cancer cells leading to the induction of apoptosis. We now demonstrate that azurin is internalized in J774 or cancer cells in a temperature-dependent manner. Azurin shows preferential entry into cancer compared with normal cells. An 28-amino-acid fragment of azurin fused to glutathione S-transferase (GST) or the green fluorescent protein (GFP), which are incapable of entering mammalian cells by themselves, can be internalized in J774 or human melanoma or breast cancer cells at 37 degrees C, but not at 4 degrees C. Competition experiments as well as studies with inhibitors such as cytochalasin D suggest that azurin may enter cells, at least in part, by a receptor-mediated endocytic process. The 28-amino-acid peptide therefore acts as a potential protein transduction domain (PTD), and can be used as a vehicle to transport cargo proteins such as GST and GST-GFP fusion proteins. Another member of the cupredoxin family, rusticyanin, that has also been shown to enter J774 and human cancer cells and exert cytotoxicity, does not demonstrate preferential entry for cancer cells and lacks the structural features characteristic of the azurin PTD.
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PMID:Internalization of bacterial redox protein azurin in mammalian cells: entry domain and specificity. 1615 42

Subtraction hybridization applied to terminally differentiating human melanoma cells identified mda-7/IL-24, a cytokine belonging to the IL-10 gene superfamily. Adenoviral-mediated delivery of mda-7/IL-24 (Ad.mda-7) provokes apoptosis selectively in a wide spectrum of cancers in vitro in cell culture, in vivo in human tumor xenograft animal models and in patients with advanced carcinomas and melanomas. In human prostate cancer cells, a role for mitochondrial dysfunction and induction of reactive oxygen species in the apoptotic process has been established. Ectopic overexpression of bcl-xL and bcl-2 prevents these changes including apoptosis induction in prostate tumor cells by Ad.mda-7. We now document that this resistance to apoptosis can be reversed by treating bcl-2 family overexpressing prostate tumor cells with ionizing radiation in combination with Ad.mda-7 or purified GST-MDA-7 protein. Additionally, radiation augments apoptosis induction by mda-7/IL-24 in parental and neomycin-resistant prostate tumor cells. Radiosensitization to mda-7/IL-24 is dependent on JNK signaling, as treatment with the JNK 1/2/3 inhibitor SP600125 abolishes this effect. Considering that elevated expression of bcl-xL and bcl-2 are frequent events in prostate cancer development and progression, the present studies support the use of ionizing radiation in combination with mda-7/IL-24 as a means of augmenting the therapeutic benefit of this gene in prostate cancer, particularly in the context of tumors displaying resistance to radiation therapy owing to bcl-2 family member overexpression.
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PMID:Ionizing radiation enhances therapeutic activity of mda-7/IL-24: overcoming radiation- and mda-7/IL-24-resistance in prostate cancer cells overexpressing the antiapoptotic proteins bcl-xL or bcl-2. 1633 Dec 61

Using 2-DE of total cell protein extracts, we compared soluble proteins from murine melanoma lines Tm1 and Tm5 with proteins from the nontumoral cell melan-a from which they were derived. Seventy-one of the 452 spots (average) detected with CBB were differentially accumulated, i.e., increased or decreased twofold. Forty-four spots were identified by PMF/MALDI-TOF, 15 with increased and 29 with decreased protein levels. SAGE showed that 17/34 (50%) of the differentially accumulated proteins, pI range 4-7, presented similar differences at the mRNA level. Major reductions in protein were observed in tumor cells of proteins that degrade reactive oxygen species (ROS). Decreases of > or = twofold in GST, superoxide dismutase, aldehyde dehydrogenase, thioredoxin, peroxiredoxin 2, and peroxiredoxin 6 protein were observed. SAGE indicated the reduction of other proteins involved in ROS degradation. As expected, the accumulation of exogenous peroxides was significantly higher in the tumor cells while the levels of glutathionylation were two times lower in the tumor cells compared to melan-a. The differential accumulation of proteins involved in oncogene/tumor suppressor pathways was observed. Melanoma cells can favor survival pathways activated by ROS by inhibiting p53 pathways and activation of Ras and c-myc pathways.
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PMID:Proteomic and SAGE profiling of murine melanoma progression indicates the reduction of proteins responsible for ROS degradation. 1642 58

The oral administration of extracts of young radishes cultivated with sulfur after intravenous tumor cell injection achieved a marked reduction of pulmonary colonization in mice. Treatment of the mice with extracts of young radish cultivated with sulfur did not show any increase in the number of CD8+ or NK T cells in the spleen, indicating no influence on host immunity. Sulforaphane, which could be a candidate for an active compound from young radishes cultivated with sulfur, inhibited cell growth of B16-F10 melanoma cells. In addition, extracts of the young radish cultivated with sulfur-fed group showed enhanced quinine reductase (QR) activities in the liver and lung and a slight increase of glutathione S-transferase (GST) activity in the liver. These results suggested that the administration of extracts of young radishes cultivated with sulfur suppressed pulmonary tumorigenesis, possibly due to increased activity of detoxification enzymes in the liver and lung, and partly due to cell cytotoxicity.
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PMID:Suppressive effects of young radish cultivated with sulfur on growth and metastasis of B16-F10 melanoma cells. 1659 97


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