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)

Autotaxin (ATX) is a strong motogen that can increase invasiveness and angiogenesis. In the present study, we investigated the signal transduction mechanism of ATX-induced tumor cell motility. Unlike N19RhoA expressing cells, the cells expressing N17Cdc42 or N17Rac1 showed reduced motility against ATX. ATX activated Cdc42 and Rac1 and increased complex formation between these small G proteins and p21-activated kinase (PAK). Furthermore, ATX phosphorylated focal adhesion kinase (FAK) that was not shown in cells expressing dominant negative mutants of Cdc42 or Rac1. Collectively, these data strongly indicate that Cdc42 and Rac1 are essential for ATX-induced tumor cell motility in A2058 melanoma cells, and that PAK and FAK might be also involved in the process.
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PMID:Cdc42 and Rac1 are necessary for autotaxin-induced tumor cell motility in A2058 melanoma cells. 1248 91

The tumor-suppressor p53 is a multifunctional protein mainly responsible for maintaining genomic integrity. p53 induces its tumor-suppressor activity by either causing cell-cycle arrest (G(1)/S or G(2)/M) or inducing cells to undergo apoptosis. This function of wild-type p53 as "guardian of the genome" is presumably achieved by forming molecular complexes with different DNA targets as well as by interacting with a number of cellular proteins, e.g., Mdm2, Gadd45, p21, 14-3-3sigma, Bax and Apaf-1. Upon activation, p53 activates p21, which in turn controls the cell cycle by regulating G(1) or G(2) checkpoints. Here, we report SMAR1 as one such p53-interacting protein that is involved in delaying tumor progression in vivo as well as in regulating the cell cycle. SMAR1 is a newly identified MARBP involved in chromatin-mediated gene regulation. The SMAR1 gene encodes at least 2 alternatively spliced variants: SMAR1(L) (the full-length form) and SMAR1(S) (the shorter form). We report that expression of SMAR1(S), but not of SMAR1(L), mRNA was decreased in most of the human cell lines examined, suggesting selective silencing of SMAR1(S). Overexpression of SMAR1(S) in mouse melanoma cells (B16F1) and their subsequent injection in C57BL/6 mice delays tumor growth. Exogenous SMAR1(S) causes significant retardation of B16F1 cells in the G(2)/M phase of the cell cycle compared to SMAR1(L). SMAR1(S) activates p53-mediated reporter gene expression in mouse melanoma cells, breast cancer cells (MCF-7) and p53 null cells (K562), followed by activation of its downstream effector, p21. We further demonstrate that SMAR1 physically interacts and colocalizes with p53. These data together suggest that SMAR1 is the only known MARBP that delays tumor progression via direct activation and interaction with tumor-suppressor p53.
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PMID:Direct interaction with and activation of p53 by SMAR1 retards cell-cycle progression at G2/M phase and delays tumor growth in mice. 1249 67

Due to minimal success with non-surgical treatment options for melanoma, it is imperative that other compounds be tested for potential preventive/therapeutic use. We have tested the ability of the endogenous oestrogenic metabolite 2-methoxyestradiol (2-ME) to inhibit the growth of human melanoma cells in culture. 2-ME inhibited the growth of all the melanoma cells tested, without inhibiting the growth of non-tumorigenic cells. Microscopic observations showed that treated cells exhibit the characteristic features of apoptosis. Examination of the molecular mechanism in WM98-1 cells, using biochemical assays such as a modified TUNEL staining and DNA fragmentation, confirmed the induction of apoptosis following 2-ME treatment. Flow cytometry analysis showed that, following treatment, cells are arrested in the G(2)/M phase of the cell cycle. Western blot analysis of the G(2)/M regulatory proteins suggests that cdc2 is involved in the cell cycle block by Myt1 phosphorylation following 2-ME treatment. Furthermore, examination of the levels of apoptosis regulatory proteins showed that, while levels of p53, Bax and p21 are higher, that of anti-apoptotic Bcl-2 is undetectable in cells treated with 2-ME compared with untreated controls. Taken together these results have major implications for the use of 2-ME for melanoma management.
Melanoma Res 2003 Apr
PMID:Cell cycle block and apoptosis induction in a human melanoma cell line following treatment with 2-methoxyoestradiol: therapeutic implications? 1269 Feb 94

Melanoma begins with benign nevi and progresses to radial growth phase (RGP) and to vertical growth phase [(VGP), metastatic phenotype]. The molecular changes associated with these transitions are not yet well defined. However, transcriptional regulation of some genes that are critical in melanoma progression is beginning to be elucidated. The first part of this review will focus on our recent studies demonstrating that progression of human melanoma is associated with loss of expression of the transcription factor AP-2. In metastatic melanoma cells, this loss resulted in overexpression of MCAM/MUC18 and MMP-2, and lack of expression of c-KIT. In further investigations, we inactivated AP-2 in SB-2 primary cutaneous melanoma cells by using a dominant-negative AP-2, 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. We have also recently demonstrated that loss of AP-2 expression in metastatic melanoma cells resulted in overproduction of the thrombin receptor, PAR-1. Other studies have shown that AP-2 regulates additional genes involved in melanoma development and progression, including E-cadherin, p21/WAF-1, HER2, Bcl-2, FAS/APO-1, IGF-R-1, and VEGF. We propose that loss of AP-2 is crucial in the development of malignant melanoma. Additionally, the transition of melanoma cells from RGP to VGP is associated with overexpression of two transcription factors, CREB and ATF-1, both of which may act as survival factors for human melanoma cells. The second part of the review will briefly discuss the role of other transcription factors, including ATF-2, SNAIL, MITF, and NFkappaB in the progression of human melanoma and will summarize recent knowledge on how changes in the expression of these transcription factors contribute to acquisition of the metastatic phenotype in human melanoma.
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PMID:Transcriptional regulation of metastasis-related genes in human melanoma. 1274 83

Although activated macrophages destroy cancer cells more effectively than normal cells, the facility to escape activated macrophages is a characteristic of tumor cells. One of the mechanisms responsible for the specific killing of tumor cells by macrophages is the production of the cytokine tumor necrosis factor alpha (TNF). Therefore, resistance to TNF may provide such cancer cells a selective advantage against host elimination. In the present work we explore the possibility that cyclin D1 overrides the cytostatic effect of TNF. We show that TNF induces p21(waf1) protein in malignant melanoma A375 cells and its binding to CDK2/4 and 6 proteins, and thereby inhibiting the activity of these complexes. This inhibition leads the cells to a G1 arrest. Overexpression of cyclin D1 in these cells makes them insensitive to TNF treatment with the recovery of CDK activity, however, is unable to overcome the inhibitory action of etoposide blocking the cells on G2/M. The bypass of TNF-induced G1 arrest seems to be related to the increase in the stability of cyclin D bound CDK complexes, increasing the total amount of CDK2/4 and 6 complexes and leading to a functional down titration of the p21(waf1) molecules. In these conditions the TNF-induced increase of p21(waf1) is not sufficient to inhibit the high amount of cyclin D-bound complexes. This hypothesis is supported by the fact that a reduction in the levels of p21(waf1) protein, induced by the expression of a mRNA antisense against p21(waf1), is also able to bypass of TNF-induced arrest. Our results confirm that p21(waf1) has an essential role in TNF-induced arrest and that the deregulation of cyclin D1 may be one of the mechanisms to escape physiological signals to restrict tumoral growth.
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PMID:Overexpression of cyclin D1 inhibits TNF-induced growth arrest. 1276 82

Transforming growth factor-beta (TGF-beta ) has dual and paradoxical functions as a tumor suppressor and promoter of tumor progression and metastasis. TGF-Ji-mediated growth inhibition is gradually lost during melanoma tumor progression, but there are no measurable defects at the receptor level. Furthermore, melanoma cells release high levels of TGF-beta to the microenvironment, which upon activation induces matrix deposition, angiogenesis, survival, and transition to more aggressive phenotypes. The SKI and SnoN protein family associate with and repress the activity of Smad2, Smad3, and Smad4, three members of the TGF-fl signaling pathway. SKI also facilitates cell-cycle progression by targeting the RB pathway by at least two ways: it directly associates with RB and represses its activity when expressed at high levels, and indirectly, it represses Smad-mediated induction of p21(Waf-1) This results in increased CDK2 activity, RB phosphorylation,and inactivation. Therefore, high levels of SKI result in lesions to the RB pathway in a manner similar to p16 (INK4a) loss. SKI mRNA and protein levels dramatically increase during human melanoma tumor progression. In addition,the SKI protein shifts from nuclear localization in intraepidermal melanoma cells to nuclear and cytoplasmic in invasive and metastatic melanomas. Here, I discuss the basis for repression of intracellular TGF-beta signaling by SKI, some additional activities of this protein, and propose that by disrupting multiple tumor suppressor pathways, SKI functions as a melanoma oncogene.
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PMID:Repression of TGF-beta signaling by the oncogenic protein SKI in human melanomas: consequences for proliferation, survival, and metastasis. 1279 38

Abnormalities in the cell cycle are responsible for the majority of human neoplasias. Most abnormalities occur due to hyperphosphorylation of the tumor suppressor gene Rb by the key regulators of the cell cycle, the cyclin-dependent kinases (CDKs). Thus, a pharmacological CDK inhibitor may be useful in the prevention and/or treatment of human neoplasms. Flavopiridol is a flavonoid with interesting preclinical properties: (1) potent CDK inhibitory activity; (2) it depletes cyclin D1 and vascular endothelial growth factor mRNA by transcriptional and posttranscriptional mechanisms, respectively; (3) it inhibits positive elongation factor B, leading to transcription "halt"; and (4) it induces apoptosis in several preclinical models. The first phase I trial of a CDK inhibitor, flavopiridol, has been completed. Dose-limiting toxicities included secretory diarrhea and proinflammatory syndrome. Antitumor activity was observed in some patients with non-Hodgkin's lymphoma and renal, colon, and prostate cancers. Concentrations between 300 and 500 n M-necessary to inhibit CDK-were achieved safely. Phase II trials with infusional flavopiridol and phase I infusional trials in combination with standard chemotherapy are being completed with encouraging results. A novel phase I trial of 1-h flavopiridol administration was recently completed. The maximum tolerated doses using flavopiridol daily for 5, 3, and 1 consecutive days are 37.5, 50, and 62.5 mg/m(2) per day. Dose-limiting toxicities include vomiting, neutropenia, proinflammatory syndrome, and diarrhea. Plasma flavopiridol concentrations achieved were in the range 1.5-3.5 MICRO M. Phase II/III trials using this 1-h schedule in several tumor types including non-small-cell lung cancer, chronic lymphocytic leukemia, mantle cell lymphoma, and head and neck cancer are being conducted worldwide. UCN-01, the second CDK modulator that has entered clinical trials, has unique preclinical properties: (1) it inhibits protein kinase C (PKC) activity; (2) it promotes cell-cycle arrest by accumulation in p21/p27; (3) it induces apoptosis in several preclinical models; and (4) it abrogates the G(2) checkpoint by inhibition of chk1. The last of these represents a novel strategy to combine UCN-01 with DNA-damaging agents. In the initial UCN-01 clinical trial (continuous infusion for 72 h), a prolonged half-life of about 600 h (100 times longer than in preclinical models) was observed. The maximum tolerated dose was 42.5 mg/m(2) per day for 3 days. Dose-limiting toxicities were nausea/vomiting, hypoxemia, and symptomatic hyperglycemia. One patient with melanoma achieved a partial response (8 months). Another patient with refractory anaplastic large-cell lymphoma had no evidence of disease at >4 years. Bone marrow and tumor samples obtained from some patients revealed loss in adducin phosphorylation, a substrate of PKC. Phase I trials with shorter infusions are being completed. In summary, the first two CDK modulators have shown encouraging results in early clinical trials. A question that remains unanswered is "Which is the best schedule for combination with standard antitumor agents?" Moreover, it is still unclear which pharmacodynamic endpoint reflects loss of CDK activity in tissue samples from patients in these trials. Despite these caveats, we feel that CDKs are sensible targets for cancer therapy and that there are several small-molecule CDK modulators in clinical trials with encouraging results.
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PMID:Novel direct and indirect cyclin-dependent kinase modulators for the prevention and treatment of human neoplasms. 1281 36

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

Malignant melanomas are frequently characterized by elevated levels of wild-type p53, suggesting that p53 function could be suppressed by a mechanism different from p53 mutation. We analysed the functionality of the p53-signaling pathway in a panel of seven human melanoma cell lines consisting of one p53-deficient line, two lines with mutant p53, and four lines expressing wild-type p53. Only lines with wild-type p53 were characterized by elevated levels of endogenous p21, high activity of p53-responsive reporters and accumulation of p53 in response to genotoxic stress, common properties of functional p53. The presence of wild-type p53 was associated with depletion or loss of p14ARF and p16 expression. The levels of p33ING1b and p24ING1c, two major products of Ing1 locus and putative coregulators of p53, were elevated in all cell lines tested; however, ectopic expression of either ING1 isoform had no effect on cell proliferation. All lines retained expression of Apaf-1, and all but one remained sensitive to ectopic expression of retrovirus-transduced p53. Our data indicate that regardless of abnormally high levels of p53 in melanomas, their p53 remains competent in transactivation of its targets, and, if highly overexpressed, capable of growth inhibition. Hence, the p53 pathway in malignant melanomas can be considered for pharmacological targeting and anticancer gene therapy.
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PMID:Melanoma cells can tolerate high levels of transcriptionally active endogenous p53 but are sensitive to retrovirus-transduced p53. 1289 34

Aberrations of chromosome 9 p21-22 are involved in the genesis of many forms of cancer. The gene p16 and p15 have been assigned to this region. Both p16 and p15 are an inhibitor of cyclin D-cdk4,cyclin D-cdk6 complex and have been implicated in a wide variety of cancer types, including the germline of patients with familial melanoma. In order to investigate and compare the status of p16,p15 gene in primary tumors and cell lines, we examined 357 primary tumors and 29 cell lines derived from diverse tumor types. In addition to analysis of these primary tumors and cell lines, blood specimens from 91 patients either with sporadic multiple cancers or from cancer-prone families were also analyzed. The data showed the following: 1) Homozygous deletions of p16,p15 were comparatively rare and far less common than previously reported, although hemizygous deletions were observed in a significant fraction of many tumor types; 2) the incidence of p16,p15 deletions (either homozygous deletions or heterozygous deletions) varied significantly among different tumor types; 3) most deletions involved in both p16 and p15 genes; 4) sequence variations in the coding sequence of p16,p15 were comparatively rare among these tumor types, though mutations and polymorphisms were identified; 5) some tumors which showed LOH at 9p, containing p16 and p15 gene, did not show deletions or point mutations in the p16,p15 gene. 6) In a subset of retinoblastoma and osteosarcoma where no Rb gene mutations were present a significant fraction was found to contain p16,p15 gene deletions.
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PMID:Deletions and point mutations of p16,p15 gene in primary tumors and tumor cell lines. 1289 91


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