Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of endogenous NO on cell survival was investigated in human melanoma cells and melanocytes. Inducible NO synthase (iNOS) was always expressed in a panel of melanoma cell lines from metastatic lesions and in normal adult melanocytes. iNOS was also detected by immunohistochemistry in melanoma cells from metastases. Release of NO by tumor cells and melanocytes was inhibited by a specific iNOS inhibitor, aminoguanidine (AMG). Inhibition of endogenous NO synthesis did not affect cell cycle progression of melanoma cells but led to cell death by apoptosis, as indicated by Annexin V/propidium iodide and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assays. By contrast, iNOS inhibition by AMG did not promote apoptosis in normal adult melanocytes. A mitochondrial pathway was involved in melanoma apop tosis, as indicated by altered mitochondrial membrane potential (delta psi(m)) and down-regulation of Bcl-2 protein level after iNOS inhibition. AMG treatment triggered release of caspase-1, enzymatic activation of caspase-3, and degradation of poly(ADP-ribose) polymerase, one of the main caspase-3 substrates. Melanoma cell apoptosis induced by iNOS inhibition was completely blocked by peptide inhibitors of caspase-1 and caspase-3 (Ac-DEVD-CHO and AC-YVAD-CHO) or by an exogenous NO donor, sodium nitroprusside, or by addition of serum. Finally, comparison of control and AMG-treated melanoma cells by pathway-specific gene array analysis indicated that inhibition of NO synthesis led, before induction of apoptosis, to up-regulation of mRNA levels of genes involved in the apoptosis pathway such as Bax, caspase-1, caspase-3, caspase-6, gadd45beta, mdm2, and TRAIL. Taken together, these results indicate that melanoma cell survival is regulated by endogenous NO resulting from iNOS activity.
 ...
PMID:Antiapoptotic role of endogenous nitric oxide in human melanoma cells. 1119 80

In the current study, two specific glycosaminoglycan lyases, chondroitinase AC and chondroitinase B, were utilized to examine the roles of chondroitin sulfates and dermatan sulfate in tumor metastasis and angiogenesis. Melanoma cells (SK-MEL) or endothelial cells were treated with either medium or chondroitinase enzyme. Chondroitinase AC inhibited melanoma invasion and proliferation as well as endothelial proliferation and angiogenesis. Apoptosis of melanoma and endothelial cells, as measured by the activity of caspase-3, was also increased by chondroitinase AC, but not by chondroitinase B. Chondroitinase B inhibited endothelial and melanoma proliferation and invasion, but to a lesser extent than chondroitinase AC. Neither chondroitinase had a detectable effect on gelatinase secretion by melanoma cells. These results indicate that both chondroitin and dermatan sulfates regulate many cellular activities related to metastasis.
 ...
PMID:Anti-tumor activities of chondroitinase AC and chondroitinase B: inhibition of angiogenesis, proliferation and invasion. 1129 Mar 71

Melanoma cells rarely contain mutant p53 and hardly undergo apoptosis by wild-type p53. By using recombinant adenoviruses that express p53 or p53-related p51A or p73beta, we tested their apoptotic activities in melanoma cells. Yeast functional assay revealed a mutation of p53 at the 258th codon (AAA [K] instead of GAA [E]) in one cell line, 70W, out of six human melanoma cell lines analyzed (SK-mel-23, SK-mel-24, SK-mel-118, TXM18, 70W, and G361). Adenovirus-mediated transfer of p53, p51A, and/or p73beta suppressed growth and induced apoptotic DNA fragmentation of SK-mel-23, SK-mel-118, and 70W cells. Interestingly, p51A induced DNA fragmentation in them more significantly than p53 and p73beta. By Western blotting we analyzed levels of apoptosis-related proteins in cells expressing p53 family members. Apoptotic Bax and antiapoptotic Bcl-2 were not significantly upregulated or downregulated by expression of p53, p51A, or p73beta, except for p53-expressing 70W cells, which contained a larger amount of Bax protein than LacZ-expressing cells. Activation of caspase-3 was demonstrated only in p51A-expressing SK-mel-118 cells. We show here that p51A can mediate apoptosis in both wild-type and mutant p53-expressing melanoma cells more significantly than p53 and p73beta. It is also suggested that in melanoma cells (i) cellular target protein(s) other than Bcl-2 and Bax might be responsible for induction of p51A-mediated apoptosis and (ii) caspase-3 is not always involved in the apoptosis by p53 family members.
 ...
PMID:Induction of apoptosis in melanoma cell lines by p53 and its related proteins. 1167 32

All human melanoma cell lines (assessed by annexin V and TUNEL assays) were resistant to apoptosis induction by TRAIL/Apo2L protein. TRAIL/Apo2L activated caspase-8 and caspase-3, but subsequent apoptotic events such as poly(ADP-ribose) polymerase cleavage and DNA fragmentation were not observed. To probe the molecular mechanisms of cellular resistance to apoptosis, melanoma cell lines were analyzed for expression of apoptosis regulators (apoptotic protease-associated factor-1, FLIP, caspase-8, caspase-9, caspase-3, cellular inhibitor of apoptosis, Bcl-2, or Bax); no correlation was observed. TRAIL/Apo2L was induced in melanoma cell lines by IFN-beta and had been correlated with apoptosis induction. Because IFN-beta induced other gene products that have been associated with apoptosis, it was postulated that one or more IFN-stimulated genes might sensitize cells to TRAIL/Apo2L. Melanoma cell lines were treated with IFN-beta for 16-24 h before treatment with TRAIL/Apo2L. Regardless of their sensitivity to either cytokine alone, >30% of cells underwent apoptosis in response to the combined treatment. Induction of apoptosis by IFN-beta and TRAIL/Apo2L in combination correlated with synergistic activation of caspase-9, a decrease in mitochondrial potential, and cleavage of poly(ADP-ribose) polymerase. Cleavage of X-linked inhibitor of apoptosis following IFN-beta and TRAIL/Apo2L treatment was observed in sensitive WM9, A375, or WM3211 cells but not in resistant WM35 or WM164 cells. Thus, in vitro IFN-beta and TRAIL/Apo2L combination treatment had more potent apoptotic and anti-growth effects when compared with either cytokine alone in melanoma cells lines.
 ...
PMID:IFN-beta pretreatment sensitizes human melanoma cells to TRAIL/Apo2 ligand-induced apoptosis. 1209 88

Extensive labelling for the apoptotic markers calcium channel receptor P2X(7) and caspase-3 and telomerase activity was co-localized at a similar intensity in areas affected by superficial spreading melanoma obtained from 80 patients. Labelling for each of these markers also extended 2 microm from the melanoma into the keratinocyte layer of the adjacent normal epidermis. Conversely, the calcium-regulating receptors P2X(1-3) and P2Y(2) (found in normal but not neoplastic skin) were fully de-expressed within 2 microm of the melanoma but fully expressed beyond that distance. The cell adhesion protein E-cadherin (also only present in normal skin) was progressively de-expressed from a point 2 microm from the melanoma until full de-expression within the lesion. These results show that telomerase-induced proliferation and defensive apoptosis are co-localized and simultaneous processes in melanoma tissue. Melanoma cell proliferation appears to overwhelm the apoptotic defence, perhaps due to the anti-apoptotic effects of telomerase. In addition, keratinocyte regulation of the epidermis and dermis is severely compromised by the loss of E-cadherin and P2X(1-3) and P2Y(2) receptors, resulting in a lesion that is aggressive and malignant.
Melanoma Res 2003 Apr
PMID:Increased expression of apoptotic markers in melanoma. 1269 Feb 96

Malignant melanoma cells have been reported to be highly resistant to chemotherapeutic agents. To gain insight into the molecular mechanisms underlying chemotherapeutic drug resistance, we examined the role of the Bcl-2 family members Bcl-2 and Bax in cell death in the melanoma cell line G361 following stimulation with cisplatin (CDDP) or dacarbazine (DTIC). Trypan blue dye exclusion showed that both CDDP and DTIC induced death of G361 cells. Apoptotic and necrotic cell death could be distinguished by flow cytometry using combined staining with annexin V and 7-amino-actinomycin D (7-AAD). CDDP-induced cell death at a low concentration (0.6 micro g/ml) was mainly due to apoptosis (annexin V+/7-AAD-), while a mixture of apoptosis and secondary necrosis (annexin V+/7-AAD+) was found at a high concentration (6 micro g/ml). DTIC at the concentrations used induced only apoptosis. CDDP-induced apoptosis and secondary necrosis were accompanied by activation of caspase-3 and modulation of Bcl-2 family members Bcl-2 and Bax. On Western blotting Bax was seen to be upregulated with concomitant downregulation of Bcl-2. Flow cytometry, which enables measurement of protein at the single-cell level, revealed that Bcl-2+/Bax- cells were decreased, with a slight concomitant rise in Bcl-2-/Bax+ cells on stimulation with CDDP. These findings suggest that the chemotherapeutic agents CDDP and DTIC induce apoptosis and/or secondary necrosis depending on dose, probably involving the modulation of Bcl-2 family proteins.
Melanoma Res 2003 Oct
PMID:Induction of apoptosis and/or necrosis following exposure to antitumour agents in a melanoma cell line, probably through modulation of Bcl-2 family proteins. 1451 87

The cholesterol-lowering medications, statins, inhibit cellular proliferation and induce apoptosis in an array of cancer cell lines, including melanoma. We investigated the apoptotic mechanism of lovastatin on human melanoma cell lines in vitro. The cytotoxicity of statins on multiple cell lines was examined by Cell Titer 96 Aqueous One solution cell proliferation assay (MTS assay). Apoptosis was assayed by ethidium bromide and acridine orange morphologic assays, an Annexin V apoptosis detection kit and active caspase 3 assays. Farnesyl pyrophosphate and geranylgeranyl pyrophosphate add-back experiments were performed to better define the molecular mechanisms mediating lovastatin cytotoxicity. Lovastatin caused cytotoxicity in human and murine melanoma cells, but did not induce toxicity in an epidermoid carcinoma cell line A431. For human melanoma cells, lovastatin precipitated cell rounding, increased the percentage of apoptotic cells detected by ethidium bromide and acridine orange staining and by the Annexin V apoptosis detection kit, and resulted in a 50-fold increase in active caspase 3, corroborating that lovastatin induced apoptosis. Adding back geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, reversed the effects of lovastatin in A375 cells. Of the five statins tested, pravastatin was least effective in killing melanoma cells. Lovastatin induced caspase-dependent apoptosis in multiple melanoma cell lines via a geranylation-specific mechanism. This study supports a possible role of lovastatin as a therapeutic, adjuvant or chemopreventive agent for melanoma.
Melanoma Res 2005 Apr
PMID:Lovastatin-induced apoptosis in human melanoma cell lines. 1584 40

The purpose of this study is to evaluate the effect of a novel anti-apoptotic gene, survivin, on the resistance and susceptibility of human uveal melanoma cells to apoptosis induced by cisplatin. The sensitivity of human uveal melanoma cell lines to apoptosis induced by cisplatin was analyzed by caspase-3 assays. The expression of the anti-apoptotic protein, survivin, was examined by flow cytometry. Melanoma cells were transfected with either survivin cDNA or survivin anti-sense cDNA and examined for susceptibility to cisplatin-induced apoptosis. Six human uveal melanoma cell lines were incubated with or without cisplatin and cellular proliferation was determined by MTT assays. Significant growth inhibition was observed in 3 melanoma cell lines (OMM1, OCM3, and MEL 270). By contrast, 3 cell lines (OMM2.5, OMM2.3, and 92-1) were resistant to cisplatin-induced apoptosis. However, a positive association was observed between resistance to cisplatin-induced apoptosis and high expression of the anti-apoptotic protein, survivin. Up-regulation of survivin by gene transfer enhanced resistance to cisplatin-induced apoptosis, while transfection with survivin anti-sense rendered resistant melanoma cells susceptible to cisplatin. The combination of cisplatin and actinomycin D significantly decreased survivin expression and enhanced the cisplatin-induced apoptosis of uveal melanoma cells in vitro. These data indicate that resistance of some uveal melanoma cells to cisplatin-induced apoptosis is controlled by anti-apoptotic proteins, such as survivin, that are sensitive to actinomycin D treatment.
 ...
PMID:Downregulation of survivin expression enhances sensitivity of cultured uveal melanoma cells to cisplatin treatment. 1658 31

Cell-cell adhesion is considered to be important in the development and maintenance of organ tissue. The spatial association between melanocytes and keratinocytes within human epidermis is achieved by homophilic interaction of E-cadherin molecules located on adjacent cells. In contrast, downregulation of E-cadherin expression in melanoma cells is considered as a key event in metastasis. Besides the adhesive properties, E-cadherin serves as a signal receptor linking to the cadherin-catenin signaling complex. As cadherins act as negative regulators of beta-catenin, a contribution to tumor formation seems likely. In the present study, it was tested whether ectopic expression of E-cadherin triggers apoptosis in human melanoma cell lines (G-361, JPC-298, SK-Mel-13). It was found that restoration of E-cadherin caused sensitization against drug-induced apoptosis. Particularly, the release of mitochondrial cytochrome c was increased in response to staurosporine. Moreover, activation of caspase-3 and caspase-8 was elevated. Similarly, DNA fragmentation, serving as a marker for advanced apoptosis, was amplified in cells transduced with E-cadherin. Interestingly, transduction with an E-cadherin construct lacking the extracellular domain showed no modified apoptosis. In conclusion, our findings suggest therapeutic strategies that enable expression of E-cadherin in order to sensitize human melanoma cells towards apoptosis.
Melanoma Res 2006 Oct
PMID:Restoration of E-cadherin sensitizes human melanoma cells for apoptosis. 1701 88

Vitamin C has been reported to be useful in the treatment and prevention of cancer. Inconsistent effects from growth stimulation to induction of apoptosis of malignant tumor cells, however, have been reported. Melanoma is an increasingly common and potentially lethal malignancy. It was reported that melanoma cells were more susceptible to ascorbate toxicity than any other tumor cells. The mechanisms accounting for ascorbate-induced apoptosis in human melanoma cells, however, have remained unclear. This study was undertaken to investigate the effect of sodium ascorbate on cytotoxicity and apoptosis in human malignant melanoma A375.S2 cells. A375.S2 cells were incubated with a certain range of concentrations of sodium ascorbate for various time periods. In order to examine the effects of sodium ascorbate on cell proliferation, cell cycle, apoptosis and necrosis, we performed 4,6-diamidino-2-phenylindole dihydrochloride assays and flow cytometry analysis. Polymerase chain reaction was used to examine the mRNA levels of p53, p21, p27, cyclin A, cyclin E, CDK2 and CDK4, which are associated with cell cycle S-phase arrest and apoptosis. Flow cytometric analysis showed that sodium ascorbate significantly induced cell cycle arrest and apoptosis in the A375.S2 cell line in a dose-dependent manner. The increased expressions of p53 and p21, and the decreased expressions of cyclin A, cyclin E, CDK2 and CDK4, indicated the cell cycle arrest at G1/S phase after the cells had been treated with sodium ascorbate. Induction of apoptosis involved an increase in the levels of p53, p21 and cellular Ca, and a decrease in mitochondrial membrane potential and activation of caspase 3 before culminating in apoptosis in sodium ascorbate-treated A375.S2 cells.
Melanoma Res 2006 Dec
PMID:Sodium ascorbate inhibits growth via the induction of cell cycle arrest and apoptosis in human malignant melanoma A375.S2 cells. 1711 52


1 2 3 4 5 6 7 8 9 10 Next >>