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)

In our previous works, we have demonstrated that terfenadine (TEF) induces DNA damage and apoptosis in human melanoma cell lines. In this present work, we have studied the effect of histamine on viability of A375 human melanoma cells and the cell-signalling pathways through which TEF may induce its apoptotic effect. We have found that exogenous histamine stimulates A375 melanoma cell proliferation in a dose- and time-dependent manner. Moreover, TEF-induced apoptosis seems to occur via other cellular pathways independent of the histamine-signalling system since co-treatment of histamine with TEF did not protect melanoma cells from the cytotoxic effect of TEF, and alpha fluoromethylhistidine did not induce the same cytotoxic effect of TEF. In addition, we have observed that knocking down the H1 histamine receptor (HRH1) by small interference RNA approach protects melanoma cells only slightly from TEF-induced apoptosis. To explore the molecular mechanisms responsible for histamine and TEF effect on the cell growth, we analysed intracellular cyclic nucleotides and Ca(2+) levels. TEF did not modify intracellular levels of cyclic adenosine 3',5'-monophosphate and cyclic guanine 3',5'-monophosphate; however, TEF induced a very sharp and sustained increase in cytosolic Ca(2+) levels in A375 melanoma cells. On the contrary, histamine did not modulate intracellular Ca(2+). TEF-induced Ca(2+) rise and apoptosis appear to be phospholipase C (PLC) dependent since neomycin and U73122, two inhibitors of PLC, abolished cytosolic Ca(2+) increase and protected the cells completely from cell death. Furthermore, inhibition of tyrosine kinase activity by genistein blocked cytosolic Ca(2+) rise and TEF-induced apoptosis. These results suggest that TEF modulates Ca(2+) homeostasis and induces apoptosis through other cellular pathways involving tyrosine kinase activity, independently of HRH1.
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PMID:Terfenadine-induced apoptosis in human melanoma cells is mediated through Ca2+ homeostasis modulation and tyrosine kinase activity, independently of H1 histamine receptors. 1817 39

Malignant melanoma is one of the most lethal cancers. Nowadays, several anti-melanoma therapies have been employed. However, the poor prognosis and/or the increased toxicity of those treatments clearly demonstrate the requirement of searching for new drugs or novel combined chemotherapeutic protocols, contemplating both effectiveness and low toxicity. Guanosine (Guo) has been used in combination with acriflavina to potentiate the latter's antitumor activity, through still unknown mechanisms. Here, we show that Guo induces B16F10 melanoma cell differentiation, attested by growth arrest, dendrite-like outgrowth and increased melanogenesis, and also reduced motility. A sustained ERK 1/2 phosphorylation was observed after Guo treatment and ERK inhibition led to blockage of dendritogenesis. Intracellular cyclic AMP was not involved in ERK activation, since its levels remained unchanged. Protein kinase C (PKC), in contrast to phospholipase C (PLC), inhibition completely prevented ERK activation. While the classical melanoma differentiation agent forskolin activates cAMP-PKA-Raf-MEK-ERK pathway in B16F10 cells, here we suggest that a cAMP-independent, PKC-ERK axis is involved in Guo-induced B16F10 differentiation. Altogether, our results show that Guo acts as a differentiating agent, with cytostatic rather than cytotoxic properties, leading to a decreased melanoma malignancy. Thus, we propose that Guo may be envisaged in combination with lower doses of conventional anti-melanoma drugs, in an attempt to prevent or diminish their adverse effects.
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PMID:Guanosine promotes B16F10 melanoma cell differentiation through PKC-ERK 1/2 pathway. 1845 49

Chinese hamster ovary (CHO) cells expressing the human melanoma tumour antigen, p97, were used to develop a controlled release process for the production of recombinant glycosyl-phosphatidylinositol (GPI) anchored proteins. The cells were cultured either in suspension or immobilized on porous microcarriers and p97 was selectively cleaved from the cell surface by the bacterial enzyme, phosphatidylinositol-phospholipase C (PI-PLC). The kinetics of p97 cleavage from the cell surface by PI-PLC was shown to be approximated by Michaelis-Menten kinetics. The recovered p97 concentrations were increased by reusing the PI-PLC enzyme solution to harvest multiple batches of cells. A convenient PI-PLC assay was developed to monitor the harvesting process and to determine the stability of PI-PLC under harvesting conditions. Although the Pl-PLC was stable under harvesting conditions, it rapidly adsorbed to the cell surface and was depleted from the reused enzyme solution. In order to maintain PI-PLC activity, it was necessary to add fresh PI-PLC to the reused enzyme solution before harvesting a fresh batch of cells. The maximum p97 concentration that could be obtained from harvesting CHO cells cultured on porous microcarriers was limited by the dilution effects of sample removal, adding fresh PI-PLC and liquid associated with settled microcarriers. A model was developed that adequately predicted the p97 concentration after each harvest and the maximum p97 concentration that could be achieved by this harvesting method. The dilution effects were minimized by harvesting from centrifuged suspension culture cells and the harvested p97 concentration was increased by over sixfold to 0.64 mg/mL.
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PMID:Increasing GPI-anchored protein harvest concentrations from suspension and porous microcarrier CHO cell cultures. 1863 51

Myeloid dendritic cells (mDC) activated with a B7-DC-specific cross-linking IgM Ab (B7-DC XAb) take up and retain Ag and interact with T cell compartments to affect a number of biologic changes that together cause strong antitumor responses and blockade of inflammatory airway disease in animal models. The molecular events mediating the initial responses in mDC remain unclear. In this study we show that B7-DC XAb caused rapid phosphorylation of the adaptor protein DAP12 and intracellular kinases Syk and phospholipase C-gamma1. Pretreatment of mDC with the Syk inhibitor piceatannol blocked B7-DC XAb-induced Ag uptake with a concomitant loss of tumor protection in mice. Vaccination with tumor lysate-pulsed wild-type B7-DC XAb-activated mDC, but not TREM-2 knockout XAb-activated mDC, protected mice from lethal melanoma challenge. Multimolecular caps appeared within minutes of B7-DC XAb binding to either human or mouse mDC, and FRET analysis showed that class II, CD80, CD86, and TREM-2 are recruited in tight association on the cell surface. When TREM-2 expression was reduced in wild-type mDC using short hairpin RNA or by using mDC from TREM-2 knockout mice, in vitro DC failed to take up Ag after B7-DC XAb stimulation. These results directly link TREM-2 signaling with one change in the mDC phenotype that occurs in response to this unique Ab. The parallel signaling events observed in both human and mouse mDC support the hypothesis that B7-DC cross-linking may be useful as a therapeutic immune modulator in human patients.
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PMID:TREM-2 mediated signaling induces antigen uptake and retention in mature myeloid dendritic cells. 2048 97

The urokinase receptor (uPAR), expressed on the surface of many cell types, coordinates plasmin-mediated cell surface proteolysis for matrix remodeling and promotes cell adhesion by acting as a binding protein for vitronectin. There is great clinical interest in uPAR in the cancer field as numerous reports have demonstrated that up-regulation of the uPA system is correlated with malignancy of various carcinomas. Using both stable cell lines overexpressing uPAR and transient gene transfer, here we provide evidence for a non-reported role of uPAR in the phagocytosis of apoptotic cells, a process that has recently been termed efferocytosis. When uPAR was expressed in human embryonic kidney cells, hamster melanoma cells, or breast cancer cells (BCCs), there was a robust enhancement in the efferocytosis of apoptotic cells. uPAR-expressing cells failed to stimulate engulfment of viable cells, suggesting that uPAR enhances recognition of one or more determinant on the surface of the apoptotic cell. uPAR-mediated engulfment was not inhibited by expression of mutant beta5 integrin, nor was alphavbeta5 integrin-mediated engulfment modulated by cleavage of uPAR by phosphatidylinositol-specific phospholipase C. Further, we found that the more aggressive BCCs had a higher phagocytic capacity that correlated with uPAR expression and cleavage of membrane-associated uPAR in MDA-MB231 BCCs significantly impaired phagocytic activity. Because efferocytosis is critical for the resolution of inflammation and production of anti-inflammatory cytokines, overexpression of uPAR in tumor cells may promote a tolerogenic microenvironment that favors tumor progression.
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PMID:The urokinase plasminogen activator receptor promotes efferocytosis of apoptotic cells. 1938 7

The essential toxin in Clostridium perfringens-mediated gas gangrene or clostridial myonecrosis is alpha-toxin, although other toxins and extracellular enzymes may also be involved. In many bacterial pathogens extracellular sialidases are important virulence factors, and it has been suggested that sialidases may play a role in gas gangrene. C. perfringens strains have combinations of three different sialidase genes, two of which, nanI and nanJ, encode secreted sialidases. The nanI and nanJ genes were insertionally inactivated by homologous recombination in derivatives of sequenced strain 13 and were shown to encode two functional secreted sialidases, NanI and NanJ. Analysis of these derivatives showed that NanI was the major sialidase in this organism. Mutation of nanI resulted in loss of most of the secreted sialidase activity, and the residual activity was eliminated by subsequent mutation of the nanJ gene. Only a slight reduction in the total sialidase activity was observed in a nanJ mutant. Cytotoxicity assays using the B16 melanoma cell line showed that supernatants containing NanI or overexpressing NanJ enhanced alpha-toxin-mediated cytotoxicity. Finally, the ability of nanI, nanJ, and nanIJ mutants to cause disease was assessed in a mouse myonecrosis model. No attenuation of virulence was observed for any of these strains, providing evidence that neither the NanI sialidase nor the NanJ sialidase is essential for virulence.
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PMID:The NanI and NanJ sialidases of Clostridium perfringens are not essential for virulence. 1965 73

It has been shown in our previous study that melanoma cells induce junction disassembly in the manner related to phospholipase C-calcium activation. In light of this observation, we have developed a mathematical model of the signaling pathway and adapted multi-parametric sensitivity analysis (MPSA) to identify important parameters in the model, which examines tumor cell-induced calcium mobilization in endothelial cells. The objective functions, with respect to individual parameters, were generated for the calcium mobilization model and MPSA was performed according to the function. The results showed that sarco/endoplasmic reticulum calcium ATPase was one of the putative key factors in regulating calcium mobilization. The model is a proof of concept of systemic analysis of a signaling network, and the results may have practical applications in describing how endothelial cells respond to tumor cells. Taken together, we have devised numerical means to macroscopically study roles of calcium signaling in endothelial cells in contact with metastatic tumor cells.
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PMID:Systemic Analysis of Tumor Cell-Induced Endothelial Calcium Signaling and Junction Disassembly. 1991 93

Membranes are known to respond rapidly to various environmental perturbations by changing their composition and microdomain organization. In previous work we showed that a membrane fluidizer benzyl alcohol (BA) could mimic the effects of heat stress and enhance heat shock protein synthesis in different mammalian cells. Here we explore heat- and BA-induced stress further by characterizing stress-induced membrane lipid changes in mouse melanoma B16 cells. Lipidomic fingerprints revealed that membrane stress achieved either by heat or BA resulted in pronounced and highly specific alterations in lipid metabolism. The loss in polyenes with the concomitant increase in saturated lipid species was shown to be a consequence of the activation of phopholipases (mainly phopholipase A(2) and C). A phospholipase C-diacylglycerol lipase-monoacylglycerol lipase pathway was identified in B16 cells and contributed significantly to the production of several lipid mediators upon stress including the potent heat shock modulator, arachidonic acid. The accumulation of cholesterol, ceramide and saturated phosphoglyceride species with raft-forming properties observed upon both heat and BA treatments of B16 cells may explain the condensation of ordered plasma membrane domains previously detected by fluorescence microscopy and may serve as a signalling platform in stress responses or as a primary defence mechanism against the noxious effects of stresses.
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PMID:Lipidomics reveals membrane lipid remodelling and release of potential lipid mediators during early stress responses in a murine melanoma cell line. 2043 Jan 10

Melanoma has a poor prognosis due to its strong metastatic ability. Although Ca(2+) plays a major role in cell migration, little is known about the role of Ca(2+) in melanoma cell migration. We recently found that the exchange protein directly activated by cyclic AMP (Epac) increases melanoma cell migration via a heparan sulfate-related mechanism. In addition to this mechanism, we also found that Epac regulates melanoma cell migration by a Ca(2+)-dependent mechanism. An Epac agonist increased Ca(2+) in several different melanoma cell lines but not in melanocytes. Ablation of Epac1 with short hairpin RNA inhibited the Epac agonist-induced Ca(2+) elevation, suggesting the critical role of Epac1 in Ca(2+) homeostasis in melanoma cells. Epac-induced Ca(2+) elevation was negated by the inhibition of phospholipase C (PLC) and inositol triphosphate (IP(3)) receptor. Furthermore, Epac-induced cell migration was reduced by the inhibition of PLC or IP(3) receptor. These data suggest that Epac activates Ca(2+) release from the endoplasmic reticulum via the PLC/IP(3) receptor pathway, and this Ca(2+) elevation is involved in Epac-induced cell migration. Actin assembly was increased by Epac-induced Ca(2+), suggesting the involvement of actin in Epac-induced cell migration. In human melanoma specimens, mRNA expression of Epac1 was higher in metastatic melanoma than in primary melanoma, suggesting a role for Epac1 in melanoma metastasis. In conclusion, our findings reveal that Epac is a potential target for the suppression of melanoma cell migration, and, thus, the development of metastasis.
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PMID:Exchange protein directly activated by cyclic AMP increases melanoma cell migration by a Ca2+-dependent mechanism. 2055 Oct 63

We have previously shown that ectopic expression of metabotropic glutamate receptor subtype 1 in melanocytes is essential for both development and in vivo growth of melanoma using newly developed transgenic mice which conditionally express metabotropic glutamate receptor subtype 1 (mGluR1). In this study, we developed conditional transgenic mice, which harbor melanocytes not only in the dermis and hair follicles but also in the epidermis using stem cell factor transgenic mice. Pigmented plaques on the backs, tails, ears or groins of the transgenic mice began to appear 13 weeks after activation of the mGluR1 transgene, and the transgenic mice produced melanomas at a frequency of 100% 36 weeks after transgene activation. Although this transgenic mouse harbors melanocytes in the epidermis, proliferation of melanoma cells took place in the dermis. To elucidate the signals involved in development and growth of melanoma, inhibitors to phospholipase C, protein kinase C and mitogen-activated protein kinase kinase 1/2, and antagonists to Ca(2+) and calmodulin were administrated to transgenic mice. Each signal inhibitor to phospholipase, protein kinase C, Ca(2+) release, calmodulin and mitogen-activated protein kinase kinase 1/2 inhibited melanoma development. However, once melanoma was developed, the growth of melanoma was dramatically inhibited only by the inhibitor to mitogen-activated protein kinase kinase 1/2 with partial inhibition by inhibitors to protein kinase C and phospholipase C. This inhibition of melanoma growth was well correlated with the expression of phosphorylated extracellular signal-regulated kinase 1/2 and Ki-67. These results indicate that for development of melanoma, activation of every signaling pathway from mGluR1 is required. However, for growth of melanoma, the extracellular signal-regulated kinase pathway plays a key role.
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PMID:Pharmacogenomics of metabotropic glutamate receptor subtype 1 and in vivo malignant melanoma formation. 2062 30


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