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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase [(VGP), metastatic phenotype] are not very well defined. We previously demonstrated that expression of the cell-surface adhesion molecule MCAM/MUC18 correlates directly with the metastatic potential of human melanoma cells. In addition, the progression of human melanoma towards the metastatic phenotype is associated with loss of expression of the tyrosine-kinase receptor c-KIT. In this review, I will summarize our recent studies demonstrating that the expression of both genes is regulated by the AP-2 transcription factor. Moreover, we have observed a loss of AP-2 expression in metastatic melanoma cells. Re-expression of AP-2 in the highly metastatic A375SM cells decreased their tumorigenicity and inhibited their metastatic potential in nude mice. MCAM/MUC18 mRNA and protein expression was significantly down-regulated while c-KIT expression was up-regulated in the AP-2-transfected cells. To further investigate the role of AP-2 in the progression of human melanoma, we attempted to inactivate AP-2 in primary cutaneous melanoma by using a dominant-negative AP-2, or the AP-2B gene. Expression of AP-2B in SB-2 cells augmented their tumorigenicity in nude mice, and upregulated MMP-2 expression and activity. As AP-2 also regulates other genes that are involved in the progression of human melanoma such as E-cadherin, p21/WAF-1, HER2/neu, Bcl-2, FAS/APO-1, IGF-R-1, VEGF and the thrombin receptor (PAR-1), we therefore propose that loss of AP-2 is a crucial event in the development of malignant melanoma. In addition, the transition of melanoma cells from RGP to VGP is also associated with over-expression of the transcription factors CREB and ATF-1. The notion that the balance between AP-2 and CREB/ATF-1 expression determines the progression of melanoma cells towards the metastatic phenotype will be discussed.
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PMID:Gene regulation in melanoma progression by the AP-2 transcription factor. 1131 Jul 95

We have investigated the effects of a series of flavonoids on cell proliferation and cell cycle distribution in human melanoma cells OCM-1. Among the compounds that potently inhibited OCM-1 cell proliferation, we show that the presence of a hydroxyl group at the 3'-position of the ring B in quercetin and luteolin, correlated to a G1 cell cycle arrest while its absence in kaempferol and apigenin correlated to a G2 block. Genistein with a hydroxyl at 5-position of the ring A arrested cells in G2 while daidzein which lacks it, induced an accumulation of cells in G1. We demonstrate that flavonoids, which induced a cell cycle block in G1, inhibited the activity of CDK2 by 40-60%. By contrast, those which caused an accumulation of cells in G2/M were without effect. On the other hand, while quercetin, daidzein and luteolin did not alter the activity of CDK1, kaempferol, apigenin and genistein inhibited this kinase by 50-70%. We demonstrate that the up-regulation of the CDK inhibitors p27(KIP1) and p21(CIP1) is likely responsible for the inhibition of CDK2 while inhibition of CDK1 was rather due to the phosphorylation of the kinase on Tyr15 residue.
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PMID:Effects of structurally related flavonoids on cell cycle progression of human melanoma cells: regulation of cyclin-dependent kinases CDK2 and CDK1. 1132 24

Melanoma transformation progresses in a multistep fashion from precursor lesions such as congenital naevi. Exposure to ultraviolet (UV) light promotes this process. Betulinic acid (BA) was identified by our group as a selective inhibitor of melanoma that functions by inducing apoptosis. The present study was designed to investigate the effect of BA and UV-C (254 nm) on cultured congenital melanocytic naevi (CMN) cells, using the single-cell gel electrophoresis (comet) assay to detect DNA damage. Exposure to UV light induced a 1.7-fold increase in CMN cells (P = 0.008) when compared with controls. When a p53 genetic suppressor element that encodes a dominant negative polypeptide (termed GSE56) was introduced into the CMN cells, the transfected cells were more sensitive to UV-induced DNA breakage. This suggests that p53 can protect against UV-induced DNA damage and subsequent melanoma transformation. Pretreatment with BA (3 microm) for 48 h resulted in a 25.5% reduction in UV-induced DNA breakage in the CMN cells (P = 0.023), but no changes were observed in the transfected cells. However, Western blot analysis revealed no changes in the p53 or p21 levels in BA-treated cells, suggesting that BA might mediate its action via a non-p53 pathway. These data indicate that BA may have an application as a chemopreventive agent in patients with congenital naevi.
Melanoma Res 2001 Apr
PMID:Betulinic acid reduces ultraviolet-C-induced DNA breakage in congenital melanocytic naeval cells: evidence for a potential role as a chemopreventive agent. 1133 33

Mutations in the p53 tumor suppressor gene are implicated in defective apoptotic response of tumors to genotoxic damage and, thus, are major determinants of resistance to a variety of anticancer agents. Because even melanomas harboring wild-type (wt) p53 show an abnormal response to radiation and p53 mutations occur late during melanoma progression, we investigated whether the effect of the bcl-2/bcl-xL bispecific antisense oligonucleotide 4625 is dependent on the p53 status in human C8161 melanoma cells. Upon treatment with oligonucleotide 4625, p53-mut C8161 cells showed earlier DNA damage, which occurred concomitantly with the reduction of bcl-2 and bcl-xL expression and the increase in the expression of proapoptotic bax. Loss of cell viability, bcl-2 down-regulation, and poly(ADP-ribose) polymerase cleavage, indicative of apoptosis, also occurred in wt p53 C8161 cells on treatment with oligonucleotide 4625. These effects, however, were mediated by strong induction of p53 without changes in p21 WAF1 expression in wt p53 cells, whereas a 70% decrease in p21 WAF1 expression was observed in mut p53 cells. In contrast to many other anticancer agents to which the apoptotic response is decreased because of p53 mutations, our data suggest that the bcl-2/bcl-xL bispecific antisense oligonucleotide 4625 effectively induces p53-independent apoptosis in human C8161 melanoma cells.
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PMID:p53-Independent induction of apoptosis in human melanoma cells by a bcl-2/bcl-xL bispecific antisense oligonucleotide. 1135 Sep 16

Metastasis and invasion are key steps in the systemic spread of tumor cells. To identify the genes involved in this process we recently selected highly invasive and weakly invasive cell clones from a melanoma cell line. Both cell clones showed a stable phenotype over more than 40 passages and previous analyses revealed a fivefold difference in their invasive potential in vitro and in tumorigenesis in vivo. To compare gene expression of the two cell clones a cDNA array system (Clontech human cancer cDNA array) was used. Exact quantification of differentially expressed genes in each cell clone was performed by real-time RT-PCR. An evaluation of the array data revealed a total of 36 genes that were more than 1.5-fold differentially expressed, and 26 (72%) of these showed a differential expression pattern by quantitative RT-PCR. Previously known differences in expression patterns, including loss of p16 and HLA I, or equal expression of p73, and RAR alpha, beta and gamma were confirmed by the array data. In addition, reduced expression levels of several cytoskeletal proteins, such as vimentin, gamma-actin, desmin and cytokeratins, in the highly invasive cell clone were reproducibly identified. Other genes strongly upregulated in the highly invasive cell clone included jagged 2, STAT1, tPA and c-myc, whereas MDA-6 (p21), caspase 2 and semaphorin were found to be downregulated. In conclusion, comparative hybridization of cDNA arrays identified a series of novel invasion-associated changes in gene expression and confirmed previously known expression patterns.
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PMID:Isolation of invasion-associated cDNAs in melanoma. 1148 May 87

Characteristic genetic changes underlying the metastatic progression of malignant melanoma is incompletely understood. The goal of our study was to explore specific chromosomal alterations associated with the aggressive behavior of this neoplasm. Comparative genomic hybridization was performed to screen and compare genomic imbalances present in primary and metastatic melanomas. Sixteen primary and 12 metastatic specimens were analyzed. We found that the pattern of chromosomal aberrations is similar in the two subgroups; however, alterations present only in primary and/or metastatic tumors were also discovered. The mean number of genetic changes was 6.3 (range 1-14) in primary and 7.8 (range 1-16) in metastatic lesions. Frequent losses involved 9p and 10q, whereas gains most often occurred at 1q, 6p, 7q, and 8q. Distinct, high-level amplifications were mapped to 1p12-p21 and 1p22-p31 in both tumor types. Amplification of 4q12-q13.1, 7q21.3-qter and 8q23-qter were detected only in primary tumors. The 20q13-qter amplicon was present in a metastatic tumor. The number of genetic alterations were significantly higher in primary tumors which developed metastases within one year after the surgery compared to tumors without metastasis during this time period. Fluorescence in situ hybridization with centromeric and locus-specific probes was applied to validate CGH results on a subset of tumors. Comparison of FISH and CGH data gave good correlation. The aggressive behavior of melanoma is associated with accumulation of multiple genetic alterations. Chromosome regions, which differ in the primary and metastatic lesions, may represent potential targets to identify metastases-related chromosomal alterations.
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PMID:Chromosomal imbalances in primary and metastatic melanomas revealed by comparative genomic hybridization. 1151 55

Retinoic acid (RA) induces differentiation of S91 melanoma cells through activation of RA receptor (RAR)gamma without affecting cell viability. The novel RARgamma-agonist CD437 (AHPN), however, also induces concomitant apoptosis through an unknown mechanism which was investigated here. By utilizing DNA microarray analysis, five apoptosis-associated, CD437-induced transcripts (CITs) were identified. Interestingly, all CITs are also regulated by p53 in a DNA damage response, and consistent with this interpretation, CD437 was found to cause DNA adduct-formation. However, p53 is not required for CD437-dependent regulation of CITs. Among this set of genes, induction of p21(WAF1/CIP1) is likely to be responsible for early S-phase growth-arrest of CD437-treated cells, whereas ei24 is a critical mediator of CD437-induced apoptosis in S91 cells. These data suggest an RAR-independent mechanism in which CD437 causes DNA adduct-formation, resulting in induction of a p53-independent DNA damage response, and subsequent growth-arrest and apoptosis. CD437-mediated DNA adduct-formation may also explain its apoptotic effects in other cell types.
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PMID:Retinoic acid receptor-independent mechanism of apoptosis of melanoma cells by the retinoid CD437 (AHPN). 1152 43

The small GTP-binding protein Rac is a downstream effector of the oncogene product p21-ras. Rac is involved in actin polymerization, Jun kinase activation, and intracellular superoxide anion production, through distinct pathways in tumor cells. Here we investigated the role of activated Rac in the response of tumor cells to apoptosis triggered by anti-cancer drugs or the cell surface death receptor CD95. Using M14 melanoma cells stably transfected with a constitutively active form of Rac1, we show that activated Rac inhibits tumor cell response to apoptosis. The inhibitory effect of activated Rac on apoptotic signaling is mediated by the interaction of Rac with intracellular oxidase and the subsequent production of superoxide, which is supported by experiments performed with M14 and NIH3T3 cells transiently transfected with the loss-of-function mutants of Rac in an activated RacV12 background. Consistent with these findings, we also demonstrate that inhibition of the Rac pathway in the HaRas-expressing T24 bladder carcinoma cell line induces a decrease in superoxide anion concentration, and results in a significant increase in tumor cell sensitivity to apoptosis. These findings demonstrate the existence of a novel Rac-dependent survival pathway mediated by intracellular superoxide in tumor cells.
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PMID:Activation of the RacGTPase inhibits apoptosis in human tumor cells. 1159 37

The AP-2 transcription factor plays a pivotal role in regulating the expression of several genes involved in tumor growth and progression of melanoma. We determined, by Western blot, variation in the level of expression of AP-2 and three of its downstream targets, c-kit, E-cadherin, and p21 in several human melanoma cell lines and, by immunohistochemistry, in a group of 99 histological samples including benign and malignant melanocytic lesions. A significant negative correlation between AP-2 expression level and tumor thickness was found. Moreover, AP-2 expression was positively associated with E-cadherin and c-kit expression. In contrast, there was a significant negative association between AP-2 and p21 expression levels. These findings suggest that p21 is independent of AP-2 transactivator function during the latest phases of melanoma progression. Finally, AP-2, c-kit, E-cadherin, and p21 expression levels did not show to be able to distinguish between dysplastic nevi and nevi without dysplasia. We conclude that changes in the expression of these proteins are involved in the later phases of melanoma progression, and may be responsible for the transition from local invasive melanoma to metastasis.
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PMID:Expression of AP-2 transcription factor and of its downstream target genes c-kit, E-cadherin and p21 in human cutaneous melanoma. 1159 5

The cell cycle regulatory events that interface with polyamine requirements for cell growth have not yet been clearly identified. Here we use specific inhibitors of polyamine biosynthetic enzymes to investigate the effect of polyamine pool depletion on cell cycle regulation. Treatment of MALME-3M cells with either the ornithine decarboxylase inhibitor alpha-difluoromethylornithine or the S-adenosylmethionine decarboxylase inhibitor MDL-73811 lowered specific polyamine pools and slowed cell growth but did not induce cell cycle arrest. By contrast, treatment with the combination of inhibitors halted cell growth and caused a distinct G1 arrest. The latter was associated with marked reduction of all three polyamine pools, a strong increase in p21(WAF1/CIP1/SDI1) (p21), and hypophosphorylation of retinoblastoma protein. All effects were fully prevented by exogenous polyamines. p21 induction preceded p53 stabilization in MALME-3M cells and also occurred in a polyamine-depleted, p53-nonfunctional melanoma cell line, indicating that p21 is induced at least in part through p53-independent mechanisms. Conditional overexpression of p21 in a fibrosarcoma cell line was shown previously to inhibit the expression of multiple proliferation-associated genes and to induce the expression of genes associated with various aspects of cell senescence and organism aging. Polyamine depletion in MALME-3M cells was associated with inhibition of seven of seven tested p21-inhibited genes and with induction of 13 of 14 tested p21-induced genes. p21 expression is also known to induce a senescence-like phenotype, and phenotypic features of senescence were observed in polyamine-depleted MALME-3M cells. Cells increased in size, appeared more granular, and expressed senescence-associated beta-galactosidase. Cells released from the polyamine inhibition lost the ability to form colonies, failed to replicate their DNA, and approximately 25% became bi- or multinucleated. These events parallel the outcome of prolonged p21 induction in fibrosarcoma cells. The results of this study indicate that polyamine pool depletion achieved by specific biosynthetic enzyme inhibitors causes p21-mediated G1 cell cycle arrest followed by p21-mediated changes in gene expression, development of a senescence-like phenotype, and loss of cellular proliferative capacity.
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PMID:Polyamine depletion in human melanoma cells leads to G1 arrest associated with induction of p21WAF1/CIP1/SDI1, changes in the expression of p21-regulated genes, and a senescence-like phenotype. 1169 89


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