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)

The clinically relevant polyamine analogue N(1),N(11)-diethylnorspermine (DENSPM) inhibits cell growth by down-regulating polyamine biosynthesis, up-regulating polyamine catabolism at the level of spermidine/spermine N(1)-acetyltransferase (SSAT), and depleting intracellular polyamine pools. Among human melanoma cell lines, the analogue causes rapid apoptosis in SK-MEL-28 cells and a sharp G(1) arrest in MALME-3M cells. This study reveals that DENSPM potently activates the mitogen-activated protein kinase (MAPK) pathways in melanoma cells and investigates the role of this response in determining cellular outcomes. Onset of apoptosis was preceded by an intense phosphorylation of the MAPKs, including extracellular signal-regulated kinase 1/2, c-Jun NH(2)-terminal kinase, and p38 in both SK-MEL-28 and MALME-3M cells. A panel of DENSPM analogues differing only in their ability to induce SSAT was used to show that MAPK activation was causally linked to induction of SSAT activity and related oxidative events. The latter was confirmed with the polyamine oxidase inhibitor MDL-75275 and the antioxidant N-acetyl-L-cysteine, which when used in combination with DENSPM, decreased MAPK activation and as previously shown, reduced apoptosis. The MAP/extracellular signal-regulated kinase-1 inhibitor PD 98059 reduced activation of all three kinases but failed to alter apoptosis in DENSPM-treated SK-MEL-28 cells. By contrast, the inhibitor prevented p21(waf1/cip1) induction and enhanced apoptosis in MALME-3M cells as indicated by accelerated caspase-3 activation and positive annexin V staining. The generality of this effect was demonstrated in DENSPM-treated A375 and LOX human melanoma cells. Taken together, the importance of the MAPK pathways in determining the biological response to DENSPM treatment is dependent on the genetic environment of the cell.
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PMID:The role of mitogen-activated protein kinase activation in determining cellular outcomes in polyamine analogue-treated human melanoma cells. 1283 50

We have previously demonstrated the anti-tumor activity of nitrosylcobalamin (NO-Cbl), an analog of vitamin B12 that delivers nitric oxide (NO) and increases the expression of tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and its receptors in human tumors. The specific aim of this study was to examine whether NO-Cbl could sensitize drug-resistant melanomas to Apo2L/TRAIL. Antiproliferative effects of NO-Cbl and Apo2L/TRAIL were assessed in malignant melanomas and non-tumorigenic melanocyte and fibroblast cell lines. Athymic nude mice bearing human melanoma A375 xenografts were treated with NO-Cbl and Apo2L/TRAIL. Apoptosis was measured by TUNEL and confirmed by examining levels and activity of key mediators of apoptosis. The activation status of NF-kappa B was established by assaying DNA binding, luciferase reporter activity, the phosphorylation status of I kappa B alpha, and in vitro IKK activity. NO-Cbl sensitized Apo2L/TRAIL-resistant melanoma cell lines to growth inhibition by Apo2L/TRAIL but had minimal effect on normal cell lines. NO-Cbl and Apo2L/TRAIL exerted synergistic anti-tumor activity against A375 xenografts. Treatment with NO-Cbl followed by Apo2L/TRAIL induced apoptosis in Apo2L/TRAIL-resistant tumor cells, characterized by cleavage of caspase-3, caspase-8, and PARP. NO-Cbl inhibited IKK activation, characterized by decreased phosphorylation of I kappa B alpha and inhibition of NF-kappa B DNA binding activity. NO-Cbl suppressed Apo2L/TRAIL- and TNF-alpha-mediated activation of a transfected NF-kappa B-driven luciferase reporter. XIAP, an inhibitor of apoptosis, was inactivated by NO-Cbl. NO-Cbl treatment rendered Apo2L/TRAIL-resistant malignancies sensitive to the anti-tumor effects of Apo2L/TRAIL in vitro and in vivo. The use of NO-Cbl and Apo2L/TRAIL capitalizes on the tumor-specific properties of both agents and represents a promising anti-cancer combination.
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PMID:Suppression of NF-kappa B survival signaling by nitrosylcobalamin sensitizes neoplasms to the anti-tumor effects of Apo2L/TRAIL. 3178 79

Phylogenetic analysis clusters caspase-12 with the inflammatory caspases 1 and 11. We analyzed the expression of caspase-12 in mouse embryos, adult organs, and different cell types and tested the effect of interferons (IFNs) and other proinflammatory stimuli. Constitutive expression of the caspase-12 protein was restricted to certain cell types, such as epithelial cells, primary fibroblasts, and L929 fibrosarcoma cells. In fibroblasts and B16/B16 melanoma cells, caspase-12 expression is stimulated by IFN-gamma but not by IFN-alpha or -beta. The effect is increased further when IFN-gamma is combined with TNF, lipopolysaccharide (LPS), or dsRNA. These stimuli also induce caspase-1 and -11 but inhibit the expression of caspase-3 and -9. In contrast to caspase-1 and -11, no caspase-12 protein was detected in macrophages in any of these treatments. Transient overexpression of full-length caspase-12 leads to proteolytic processing of the enzyme and apoptosis. Similar processing occurs in TNF-, LPS-, Fas ligand-, and thapsigargin (Tg)-induced apoptosis. However, B16/B16 melanoma cells die when treated with the ER stress-inducing agent Tg whether they express caspase-12 or not.
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PMID:Regulation of the expression and processing of caspase-12. 1288 62

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

Progression of melanoma is associated with loss of the transcription factor AP-2alpha and tyrosine-kinase receptor c-kit. However, the mechanisms by which these two proteins are down-regulated have not been fully elucidated. Fifty non-selected melanomas comprising ten superficial spreading melanomas (five exhibiting a radial growth phase and five a vertical growth phase), ten primary nodular melanomas, 30 melanoma metastases, and 16 naevi were investigated by direct sequencing analysis of the AP-2alpha and c-kit genes and by immunohistochemistry for the respective proteins. Because it has recently been demonstrated that AP-2alpha is preferentially cleaved by caspase-6 and to a lesser extent by caspase-3, immunohistochemistry for the cleaved (activated) forms of caspase-6 (c-casp-6) and caspase-3 (c-casp-3) was carried out. No mutations were identified in the c-kit gene, but three different point mutations were demonstrated in the activation motif of AP-2alpha in four tumours: one vertical growth phase superficial spreading melanoma, one nodular melanoma, and two metastases. Immunohistochemistry revealed progressive loss of the AP-2alpha and c-kit proteins in primary melanomas and metastases when compared with naevi. The decrease of both markers was more accentuated in the dermal component of all primary tumours, with c-kit more affected than AP-2alpha. All invasive melanomas and metastases expressed c-casp-6. c-casp-3 was expressed by 83% of the metastases and in the dermal component of one nodular melanoma. These findings suggest that the loss of AP-2alpha protein expression during the progression of melanoma could be related to mutation of the gene in only a small number of tumours, whereas the expression and activation of caspases, most prominently caspase-6, may be an important factor for the down-regulation of AP-2alpha protein. Furthermore, this study supports recent data that the activation of caspases does not inevitably result in apoptosis, but may also contribute to tumour progression in melanomas.
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PMID:Expression of AP-2alpha, c-kit, and cleaved caspase-6 and -3 in naevi and malignant melanomas of the skin. A possible role for caspases in melanoma progression? 1451 45

A number of hyaluronan (HA) binding proteins such as soluble CD44, receptor for hyaluronan-mediated motility (RHAMM), and metastatin inhibit tumor growth and metastasis. To determine whether the HA binding motif is the element responsible for the antitumor effect of this family of proteins, we examined the biological activity of a 42-amino acid peptide (designated as BH-P) that contains three HA binding motifs [B(X(7))B] from human brain HA binding protein. In initial experiments with cultured cells, we found that synthetic BH-P inhibited the proliferation and colony formation of tumor cells. It also blocked the growth of tumors on the chorioallantoic membranes of 10-day chicken embryos. In addition, MDA-435 melanoma cells that had been transfected with an expression vector for BH-P grew at a slower rate in nude mice than the vector-alone transfectants. Final studies revealed that the BH-P could activate caspase-8, caspase-3, and poly(ADP-ribose) polymerase and trigger the apoptosis of tumor cells. Taken together, these results suggest that the HA binding motif that is present in HA binding proteins may be responsible for the antitumor effect exerted by the members of this family.
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PMID:A peptide with three hyaluronan binding motifs inhibits tumor growth and induces apoptosis. 1452 84

TRAIL appears to be a promising anticancer agent in that it induces apoptosis in a wide range of cancer cells but not normal tissues. Sensitivity of melanoma cells to TRAIL-induced apoptosis varied considerably because of their development of various resistance mechanisms against apoptosis. We discuss in this report the potential effect of a histone deacetylase inhibitor SBHA on TRAIL-induced apoptosis. Histone deacetylase (HDAC) inhibitors regulate histone acetylation and thereby modulate the transcriptional activity of certain genes leading to cell growth arrest, cellular differentiation, and apoptosis. Suberic bishydroxamate (SBHA) is a relatively new HDAC inhibitor that induced apoptosis in the majority of melanoma cell lines through a mitochondrial and caspase-dependent pathway. This was due to its regulation of the expression of multiple proteins that are involved in either the mitochondrial apoptotic pathway (Bcl-2 family members) or the final phase of apoptosis (caspase-3 and XIAP). Co-treatment with SBHA at nontoxic doses and TRAIL resulted in a marked increase in TRAIL-induced apoptosis of melanoma, but showed no toxicity to melanocytes. SBHA appeared to sensitize melanoma to TRAIL-induced apoptosis by up-regulation of pro-apoptotic proteins in the TRAIL-induced apoptotic pathway such as caspase-8, caspase-3, Bid, Bak, and Bax, and up-regulation of the BH3 domain only protein, Bim. This, together with activated Bid, may have acted synergistically to cause changes in mitochondria. Treatment with SBHA also resulted in down-regulation of antiapoptotic members of the Bcl-2 family, Bcl-X(L) and Mcl-1, and the IAP member, XIAP. These changes would further facilitate apoptotic signaling. SBHA appeared therefore to be a potent agent in overcoming resistance of melanoma to TRAIL-induced apoptosis.
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PMID:The histone deacetylase inhibitor suberic bishydroxamate: a potential sensitizer of melanoma to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis. 1455 32

Inhibitor of apoptosis protein (IAP) is a family of intracellular proteins that plays an essential role in the regulation of apoptosis. Recently, we and others discovered a new member of this family, termed Livin. Many studies have focused on the inhibitory effect of IAPs on caspases. Here, we describe a novel regulatory mechanism by which Livin is cleaved by the caspases. Strikingly, the cleaved Livin, although containing intact baculovirus IAP repeat and RING domains, does not only lose its antiapoptotic function but also gains a proapoptotic effect. The cleavage is site specific at Asp-52 and is restricted to effector caspase-3 and -7. Most importantly, we demonstrate the role of Livin and this regulatory mechanism in the drug resistance of melanoma patients. Using primary cultures derived from melanoma patients, we found a correlation between Livin overexpression, in vitro drug resistance, and the patient's clinical response.
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PMID:Caspase-mediated cleavage converts Livin from an antiapoptotic to a proapoptotic factor: implications for drug-resistant melanoma. 1455 22

N1,N11-diethylnorspermine (DENSPM) is a polyamine analog that down-regulates polyamine biosynthesis and potently upregulates the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT). In certain cells, such as SKMEL-28 human melanoma cells, induction of SSAT is associated with rapid apoptosis. In this study, we used small interfering RNA (siRNA) to examine the role of SSAT induction in mediating polyamine pool depletion and apoptosis. siRNA duplexes were designed to target three independent sites in the SSAT mRNA coding region (siSSAT). When transfected under nontoxic conditions, two of the duplexes selectively reduced basal SSAT mRNA in HEK-293 cells by >80% and prevented DENSPM-induced SSAT mRNA by 95% in SK-MEL-28 cells. Treatment of SK-MEL-28 cells with 10 muM DENSPM in the presence of 83 nM siSSAT selectively prevented the 1400-fold induction of SSAT activity by approximately 90% and, in turn, prevented analog depletion of spermine (Spm) pools by approximately 35%. siSSAT also prevented DENSPM-induced cytochrome c release and caspase-3 cleavage at 36 h and apoptosis at 48 h as measured by annexin V staining. Overall, the data directly link analog induction of SSAT to Spm pool depletion and to caspase-dependent apoptosis in DENSPM-treated SK-MEL-28 cells. This represents the first use of siRNA technology directed toward a polyamine gene and the first unequivocal demonstration that SSAT induction initiates events leading to polyamine analog-induced apoptosis.
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PMID:Small interfering RNA suppression of polyamine analog-induced spermidine/spermine n1-acetyltransferase. 1457 65

We have reported that in A375-S2 cells, evodiamine isolated from Evodia rutaecarpa induces cell death of human melanoma, A375-S2, through two distinct pathways: apoptosis and necrosis. In the present study, we further demonstrate two different mechanisms by which evodiamine induces apoptosis and necrosis. Although caspase-1 and -10 inhibitors failed to block cell death, pan-caspase inhibitor and caspase-3, -8, and -9 inhibitors had marked inhibitory effects on apoptosis induced by 15 microM evodiamine. Furthermore, evodiamine-induced activation of caspase-3 resulted in the down-regulation of anti-apoptotic Bcl-2 expression and up-regulation of proapoptotic Bax expression. After 24 h incubation with evodiamine, no caspase inhibitor had any influence on cell death, but p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580) attenuated cell death; in contrast, extracellular signal-regulated protein kinase (ERK) MAPK inhibitor (PD98059) augmented cell death, as was further confirmed by cotreatment with SB203580 or PD98059 and pan-caspase inhibitor. Moreover, evodiamine increased the phosphorylation of p38 and decreased the expression and phosphorylation of ERK in caspase-independent necrosis. Consequently, evodiamine induced the caspase- and Bax-mediated apoptosis at an early stage, but, initiated MAPKs-dependent necrosis at a later stage.
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PMID:Intracellular regulation of evodiamine-induced A375-S2 cell death. 1460 Mar 98


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