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

It is known that melanoma develops as a consequence of multifactorial alterations. To date several studies indicate the effective implication of p16 as a tumor suppressor gene with a major role in either the development or progression of human melanoma. Deregulation of melanoma cell growth has been widely associated with mutations in the p16-cyclin D/cdk4-pRb pathway. Recently anticancer therapies are focused on restoration of p16 CDK inhibitory function and other proteins unregulated in melanoma cell cycle pathway (e.g., c-myc, p27). A combined strategy for restoration of normal homeostasis in the melanoma skin with targeted delivery of apoptosis-inducing agents does not seems to be far obtained. New class of antitumoral agents are emerging: histone deacetylase (HDAC) inhibitors have attracted much interest because of their ability to arrest cell growth, induce cell differentiation, and in some cases, induce apoptosis of cancer cells. Recently, attention has been focused on the ability of HDAC inhibitors to induce perturbation in cell cycle regulatory protein (e.g., p21(CIP1)) and down-regulation of survival signalling pathway. In the present study, we have examined the effect of valproic acid (VPA) on M14 human melanoma cell line. Here we observed that VPA induces cell cycle arrest and apoptosis sensitising melanoma cells to cis-platin and etoposide treatment. IC(50) dose (2.99 mM) of VPA was able to induce G(1) arrest (up to 75%) in association with upregulation of p16, p21 and cyclin-D1 related to Rb ipo-phosphorilation. In addition VPA activated apoptosis (50%) in M14 cells, when given alone or in combination with antitumoral agents. The ability of valproic acid to reestablished the G(1) pathway in melanoma cells suggests a potential application of VPA in melanoma therapeutic protocols.
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PMID:Valproic acid induces apoptosis, p16INK4A upregulation and sensitization to chemotherapy in human melanoma cells. 1721 82

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.
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PMID:Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products. 1747 22

The roles of the cyclin-dependent kinases Cdk2, Cdk4 and Cdk6 and their complementary cyclin partners in moving cells from a quiescent state into active DNA synthesis are presently undergoing re-evaluation. Normal cell cycling now appears possible in the absence of any of these molecular controlling factors whilst certain cell-cycle control kinases, such as Cdk4, appear to be mandatory for cancer cell growth. Here, we describe a unique relationship between proteomic expression of Cdk1 and Cdk4 in human cancer cell lines and data from clinical malignant melanoma. The relationship was not present in normal diploid keratinocytes and fibroblasts. We suggest that the much tighter spread of Cdk1/Cdk4 ratios in human cancer cells compared to normal cells may selectively benefit the cancer cell and thus provide a potential novel anticancer target.
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PMID:Proteomic co-expression of cyclin-dependent kinases 1 and 4 in human cancer cells. 1748 85

Immunotherapy can effectively suppress tumor, yet complete tumor eradication occurs infrequently. The metastatic potential of remnant tumor cells after immunotherapy and the underlying mechanisms have not been fully elucidated. Here, we report that the termination of immunotherapy strikingly increases the metastatic potential of remnant melanoma. This is mainly due to the withdrawal of IFN-gamma after immunotherapy. The relief of IFN-gamma stress led to the increase of alphavbeta3 integrin expression in B16 cells, which increased the adhesion of B16 cells to fibrinogen, fibronectin and laminin. Through alphavbeta3 signaling, the activation of FAK, upregulation of cdc2, production of active MMP-2 and MMP-9 and actin polymerization were intensified in B16 cells stimulated with ECM molecules 24 h after the withdrawal of IFN-gamma. The i.v. injection of such tumor cells into mice resulted in more metastatic tumor nodes in lung and shortened the survival of mice. The pitfall of immunotherapy termination can be remedied by the administration of recombinant CBD-HepII polypeptide of fibronectin, which effectively inhibits alphavbeta3 signaling. These findings suggest that the risk of tumor metastasis can be increased after the termination of immunotherapy, due to the withdrawal of IFN-gamma and that targeting alphavbeta3 signaling pathway can improve the therapeutic effect of immunotherapeutic approaches by reducing such metastatic risk.
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PMID:IFN-gamma withdrawal after immunotherapy potentiates B16 melanoma invasion and metastasis by intensifying tumor integrin alphavbeta3 signaling. 1847 Sep 15

In this study, we identified the most deleterious nsSNP in CDKN2A gene through structural and functional properties of its protein (p16INK4A) and investigated its binding affinity with cdk6. Out of 118 SNPs, 14 are nsSNPs in the coding region and 17 SNPs were found in the untranslated region (UTR). FastSNP suggested that 7 SNPs in the 5' UTR might change the protein expression levels. Sixty-four percent of nsSNPs are found to be damaged in PolyPhen server among the 14 nsSNPs investigated. With this effort, we modeled the mutant p16INK4A proteins based on these deleterious nsSNPs, out of which three nsSNPs associated p16INK4A had RMSD values of greater than 3.00 A with native protein. From a comparison of total energy of these three mutant proteins, we identified that the major mutation is from Aspartic acid to Tyrosine at the residue position of 84 of p16INK4A. Further, we compared the binding efficiency of both native and mutant p16INK4A with cdk6. We found that mutant p16INK4A has less binding affinity with cdk6 compared to native type. This is due to ten hydrogen bonds and eight salt bridges which exist between the native type and cdk6, whereas the mutant type makes only nine hydrogen bonds and five salt bridges with cdk6. Based on our investigation, we propose that the SNP with the ID rs11552822 could be the most deleterious nsSNP in CDKN2A gene, causing malignant melanoma, as it was well correlated with experimental studies carried out elsewhere.
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PMID:In silico analysis of structural and functional consequences in p16INK4A by deleterious nsSNPs associated CDKN2A gene in malignant melanoma. 1857 9

Microphthalmia-associated transcription factor (Mitf) is essential for melanocyte development and function and regulates anti-apoptotic Bcl2 expression. We hypothesized that cellular deficiency of Mitf can influence melanocyte survival in response to ultraviolet (UV) radiation. Primary melanocyte cultures were prepared from neonatal wild-type mice and congenic animals heterozygous for Mitf mutations Mitf (mi-vga9/+) and Mitf(Mi-wh/+) and exposed to UV irradiation. Wild-type melanocytes were more resistant to UV-induced apoptosis than melanocytes partially deficient in Mitf activity, as determined by relative levels of intracellular melanin and relative activation of Mitf target genes Tyr, Tyrp1, Dct, and Cdk2. Comparative experiments with wild-type cells and congenic albino melanocytes demonstrated that these differences are not due to differences in melanin content, implicating Mitf as a primary determinant of UV-dependent melanocyte survival. Mitf activity correlated directly with resistance to UV-induced apoptosis in melanocytes. Mitf was important not only for regulating the expression of anti-apoptotic Bcl-2 following UV irradiation, but also the expression of the pro-apoptotic BH3-only Bad protein and activation of the extrinsic apoptotic pathway. Hence, Mitf is a multifaceted regulator of UV-induced apoptosis in melanocytes.
Pigment Cell Melanoma Res 2009 Jun
PMID:Mitf dosage as a primary determinant of melanocyte survival after ultraviolet irradiation. 1919 12

Increasing evidence has confirmed that hinokitiol (beta-thujaplicin), a tropolone-related compound, exhibits anticancer activity in a variety of cancers through inhibition of cell proliferation. The present study indicates that hinokitiol selectively inhibits cell growth and DNA synthesis in FEM human melanoma cells. Hinokitiol-induced growth inhibition was associated with strong G1 cell cycle arrest. Consistent with blocking the G1-S-phase transition, hinokitiol markedly increased p27 protein levels, but caused only a moderate increase in p21, in addition to a decrease in Cdk2, cyclin E, and phosphorylated Rb. In addition, hinokitiol increased the stability of the p27 protein by inhibiting p27 phosphorylation at Thr(187) and by down-regulating Skp2 expression. siRNA knockdown of p27 abrogated hinokitiol-mediated growth inhibition, while knockdown of Skp2 exacerbated the G1 arrest. In addition to increasing Cdk inhibitor levels and decreasing cyclin A expression, hinokitiol also impaired Cdk2 function by inhibiting Cdk2 kinase activity, impeding cyclin E or A/Cdk2 binding, and inducing translocation of the Cdk2 protein complex. Taken together, our data demonstrate that the novel anticancer mechanism of hinokitiol involves accumulation of p27, down-regulation of Skp2, and impairment of Cdk2 function in FEM human melanoma cells. The therapeutic potential of hinokitiol may lead to novel cell-cycle-based anticancer strategies for malignant melanoma.
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PMID:p27-Associated G1 arrest induced by hinokitiol in human malignant melanoma cells is mediated via down-regulation of pRb, Skp2 ubiquitin ligase, and impairment of Cdk2 function. 1963 51

Stilbenes comprise a group of polyphenolic compounds, which exert inhibitory effects on various malignancies. The aim of this study was to evaluate the antitumor effects of a previously unreported stilbene derivative-3,3',4,4',5,5'-hexahydroxystilbene, termed M8-on human melanoma cells. Cell-cycle analysis of the metastatic melanoma cell line M24met showed that M8 treatment induces G(2)/M arrest accompanied with a dose- and time-dependent upregulation of p21 and downregulation of CDK-2 and leads to apoptosis. M8 induces the expression of phosphorylated p53, proteins involved in the mismatch repair machinery (MSH6, MSH2, and MLH1) and a robust tail moment in a comet assay. In addition, M8 inhibited cell migration in Matrigel assays. Shotgun proteomics and western analysis showed the regulation among others of paxillin, integrin-linked protein kinase, p21-activated kinase, and ROCK-1 indicating that M8 inhibits mesenchymal and amoeboid cell migration. These in vitro data were confirmed in vivo in a metastatic human melanoma severe combined immunodeficient (SCID) mouse model. We showed that M8 significantly impairs tumor growth. M8 also interfered with the metastatic process, as M8 treatment prevented the metastatic spread of melanoma cells to distant lymph nodes in vivo. In summary, M8 exerts strong antitumor effects with the potential to become a new drug for the treatment of metastatic melanoma.
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PMID:3,3',4,4',5,5'-hexahydroxystilbene impairs melanoma progression in a metastatic mouse model. 1995 88

Cyclin D1 belongs to a family of proteins that regulate progression through the G1-S phase of the cell cycle by binding to cyclin-dependent kinase (cdk)-4 to phosphorylate the retinoblastoma protein and release E2F transcription factors for progression through cell cycle. Several cancers, including breast, colon, and prostate, overexpress the cyclin D1 gene. However, the correlation of cyclin D1 overexpression with E2F target gene regulation or of cdk-dependent cyclin D1 activity with tumor development has not been identified. This suggests that the role of cyclin D1 in oncogenesis may be independent of its function as a cell cycle regulator. One such function is the role of cyclin D1 in cell adhesion and motility. Filamin A (FLNa), a member of the actin-binding filamin protein family, regulates signaling events involved in cell motility and invasion. FLNa has also been associated with a variety of cancers including lung cancer, prostate cancer, melanoma, human bladder cancer, and neuroblastoma. We hypothesized that elevated cyclin D1 facilitates motility in the invasive MDA-MB-231 breast cancer cell line. We show that MDA-MB-231 motility is affected by disturbing cyclin D1 levels or cyclin D1-cdk4/6 kinase activity. Using mass spectrometry, we find that cyclin D1 and FLNa coimmunoprecipitate and that lower levels of cyclin D1 are associated with decreased phosphorylation of FLNa at Ser2152 and Ser1459. We also identify many proteins related to cytoskeletal function, biomolecular synthesis, organelle biogenesis, and calcium regulation whose levels of expression change concomitant with decreased cell motility induced by decreased cyclin D1 and cyclin D1-cdk4/6 activities.
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PMID:Cyclin D1/cyclin-dependent kinase 4 interacts with filamin A and affects the migration and invasion potential of breast cancer cells. 2017 8

Inherited mutations affecting the INK4a/ARF locus (CDKN2A) are associated with melanoma susceptibility in 40% of multiple case melanoma families. Over 60 different germline INK4a/ARF mutations have been detected in more than 190 families worldwide. The majority of these alterations are missense mutations affecting p16(INK4a), and only 25% of these have been functionally assessed. There is therefore a need for an accurate and rapid assay to determine the functional significance of p16(INK4a) mutations. We reviewed the performance of several in vivo functional assays that measure critical aspects of p16(INK4a) function, including subcellular location, CDK binding and cell cycle inhibition. In this report the function of 28 p16(INK4a) variants, many associated with melanoma susceptibility were compared. We show that assessment of CDK4 binding and subcellular localization can accurately and rapidly determine the functional significance of melanoma-associated p16(INK4a) mutations. p16(INK4a)-CDK6 binding affinity was unhelpful, as no disease-associated mutation showed reduced CDK6 affinity while maintaining the ability to bind CDK4. Likewise, in silico analyses did not contribute substantially, with only 12 of 25 melanoma-associated missense variants consistently predicted as deleterious. The ability to determine variant functional activity accurately would identify disease-associated mutations and facilitate effective genetic counselling of individuals at high risk of melanoma.
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PMID:Predicting functional significance of cancer-associated p16(INK4a) mutations in CDKN2A. 2034 Jan 36


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