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)

BRAF encodes a RAS-regulated kinase that mediates cell growth and malignant transformation kinase pathway activation. Recently, we have identified activating BRAF mutations in 66% of melanomas and a smaller percentage of many other human cancers. To determine whether BRAF mutations account for the MAP kinase pathway activation common in non-small cell lung carcinomas (NSCLCs) and to extend the initial findings in melanoma, we screened DNA from 179 NSCLCs and 35 melanomas for BRAF mutations (exons 11 and 15). We identified BRAF mutations in 5 NSCLCs (3%; one V599 and four non-V599) and 22 melanomas (63%; 21 V599 and 1 non-V599). Three BRAF mutations identified in this study are novel, altering residues important in AKT-mediated BRAF phosphorylation and suggesting that disruption of AKT-induced BRAF inhibition can play a role in malignant transformation. To our knowledge, this is the first report of mutations documenting this interaction in human cancers. Although >90% of BRAF mutations in melanoma involve codon 599 (57 of 60), 8 of 9 BRAF mutations reported to date in NSCLC are non-V599 (89%; P < 10(-7)), strongly suggesting that BRAF mutations in NSCLC are qualitatively different from those in melanoma; thus, there may be therapeutic differences between lung cancer and melanoma in response to RAF inhibitors. Although uncommon, BRAF mutations in human lung cancers may identify a subset of tumors sensitive to targeted therapy.
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PMID:BRAF and RAS mutations in human lung cancer and melanoma. 1246 Sep 18

The biological actions of insulin are associated with a rapid reorganization of the actin cytoskeleton within cells in culture. Even though this event requires the participation of actin-binding proteins, the effect of filamin A (FLNa) on insulin-mediated signaling events is still unknown. We report here that human melanoma M2 cells lacking FLNa expression exhibited normal insulin receptor (IR) signaling, whereas FLNa-expressing A7 cells were unable to elicit insulin-dependent Shc tyrosine phosphorylation and p42/44 MAPK activation despite no significant defect in IR-stimulated phosphorylation of insulin receptor substrate-1 or activation of the phosphatidylinositol 3-kinase/AKT cascade. Insulin-dependent translocation of Shc, SOS1, and MAPK to lipid raft microdomains was markedly attenuated by FLNa expression. Coimmunoprecipitation experiments and in vitro binding assays demonstrated that FLNa binds constitutively to IR and that neither insulin nor depolymerization of actin by cytochalasin D affected this interaction. The colocalization of endogenous FLNa with IR was detected at the surface of HepG2 cells. Ectopic expression of a C-terminal fragment of FLNa (FLNaCT) in HepG2 cells blocked the endogenous IR-FLNa interaction and potentiated insulin-stimulated MAPK phosphorylation and transactivation of Elk-1 compared with vector-transfected cells. Expression of FLNaCT had no major effect on insulin-induced phosphorylation of the IR, insulin receptor substrate-1, or AKT, but it elicited changes in actin cytoskeletal structure and ruffle formation in HepG2 cells. Taken together, these results indicate that FLNa interacts constitutively with the IR to exert an inhibitory tone along the MAPK activation pathway.
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PMID:Interaction of filamin A with the insulin receptor alters insulin-dependent activation of the mitogen-activated protein kinase pathway. 1273 6

Signal transducers and activators of transcription (STAT) proteins nuclear translocation and transcriptional activity are regulated by diverse protein kinases in response to extracellular stimuli by cytokines, growth factors and stress. Using two melanoma-derived cell lines that exhibit marked differences in basal activities of MAPKs and PI3K-AKT, we studied changes both in STAT activities and in their sensitization to apoptosis. Activating mutations of B-RAF (T1796A) and impaired expression of PTEN are detected in LU1205, but not in FEMX melanoma cells, and are reflected in high basal levels of expression and activities of MAPKs and PI3K-AKT. Treatment with either PD98059 (PD) or LY294002 (LY), the pharmacological inhibitors of MEK-ERK and PI3K, respectively, markedly increased GAS-Luc activity in LU1205, but not in FEMX cells. Tyrosine phosphorylation of STAT3/5 and of JAK2 also increased upon treatment of LU1205 cells with either PD or LY, suggesting that constitutive active MAPK and PI3K signals inhibit tyrosine phosphorylation of JAK/STATs. Treatment of FEMX and LU1205 with PD sensitized the cells to apoptosis, albeit by TNFalpha and TRAIL death cascades, respectively, indicating that additional yet distinct targets are affected by each signaling pathway. Indeed, the combination of LY and PD treatment synergistically increased the apoptosis of LU1205 and FEMX cells. Overall, whereas PI3K and MAPK downregulate JAK-STAT signaling, additional targets are affected by these kinases and sensitizes melanoma to apoptosis via distinct death cascades.
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PMID:ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells: implications towards sensitization to apoptosis. 1282 43

Alteration in the expression of invasion/metastasis-related melanoma cell adhesion molecule (MelCAM) is strongly associated with the acquisition of malignancy by human melanoma. However, little is known about the molecular and biochemical mechanisms that regulate the expression and function of MelCAM, or its downstream signaling transduction. In this study, we show that there is a reciprocal regulation loop between AKT and MelCAM. Pharmacological inhibition of AKT in human melanoma cell lines substantially reduced the expression of MelCAM. Overexpression of constitutively active AKT upregulated the levels of MelCAM in melanoma cell lines, whereas expression of a dominant-negative PI-3 kinase downregulated MelCAM. On the other hand, overexpression of MelCAM activated endogenous AKT and inhibited proapoptotic protein BAD in melanoma cells, leading to increased survival under stress conditions. Constitutive activation of AKT was observed in most melanoma cell lines and tumor samples of different progression stages. These data link AKT activation with MelCAM expression, and implicate that intervention of MelCAM-AKT signaling axis in melanoma is a potential therapeutical approach.
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PMID:Reciprocal regulation of MelCAM and AKT in human melanoma. 1453 36

In B16 melanoma cells, cyclic adenosine monophosphate inhibits the phosphatidylinositol-3-kinase and the phosphatidylinositol-3-kinase inhibitor, LY294002, stimulates melanogenesis. However, the molecular mechanisms, by which phosphatidylinositol-3-kinase inhibition increases melanogenesis remained to be identified. In this study, we show that LY294002 up-regulates the expression of the melanogenic enzymes, tyrosinase and Tyrp1, through a transcriptional mechanism that involves microphthalmia associated transcription factor, a basic helix-loop-helix transcription factor, which plays a key role in melanocyte survival and differentiation. Further, we observe that LY294002 increases the intracellular content of microphthalmia associated transcription factor, thereby demonstrating that microphthalmia associated transcription factor is also a convergence point of the phosphatidylinositol-3-kinase signaling pathway. Finally, our results indicate that LY294002 controls microphthalmia associated transcription factor at the transcriptional level through distal regulatory element that remain to be identified. Interestingly, we have recently reported that cAMP-elevating agents, through a phosphatidylinositol-3-kinase/AKT inhibition and a glycogen synthase kinase 3beta activation, may stimulate microphthalmia associated transcription factor binding to its target sequence, suggesting that inhibition of the phosphatidylinositol-3-kinase is implicated in the stimulation of melanogenesis at different levels. Thus, the results presented in this report strengthen the importance of the phosphatidylinositol-3-kinase pathway in the regulation of melanogenesis and emphasize the complexity of the cyclic adenosine monophosphate signaling that controls melanocyte differentiation and melanogenesis.
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PMID:Microphthalmia associated transcription factor is a target of the phosphatidylinositol-3-kinase pathway. 1463 2

The protein synthetic machinery is activated by a variety of genetic alterations during tumor progression and represents an attractive target for cancer therapy. The mammalian target of rapamycin (mTOR) plays an important role in regulating protein translation through phosphorylation of p70 S6 kinase 1 (S6K1), a protein involved in ribosome biogenesis, and 4E-BP1 (eIF-4E binding protein), a translation repressor. It has been shown that mTOR has a direct linkage to the phosphatidylinositol-3'-kinase (PI3K)/PTEN-AKT survival pathway. Recent studies have demonstrated that mTOR inhibition by rapamycin or its analogues have remarkable activity against a wide range of human cancers in vitro and in human tumor xenograft models. Phase I clinical evaluations also suggested an anti-tumor effect of rapamycin analogue such as CCI-779. The clinical challenge for the application of this class of anticancer drug is the ability to prospectively identify which tumors will be sensitive to mTOR inhibition. Recent studies have identified cellular markers that are associated with the in vitro activity of rapamycin or CCI-779. However, there have been no reports on how these cellular markers are expressed together in human tumor specimen. In this study, multiple components of the PI3K/PTEN-AKT-mTOR pathway were evaluated by immunohistochemistry in tissue arrays containing 124 tumors from 8 common tumor types. The results show variable expression of all the signaling proteins. For example, mTOR expression was low in brain tumors, but high in the rest of tumors. High levels of 4E-BP1 were seen in colonic adenocarcinoma and low levels in lymphoma. Phospho-AKT (p-AKT) and phospho-S6K1 (p-S6K1) were the only proteins that had significantly correlated protein expression (rs=0.51, p<0.001). Since low PTEN, high p-AKT and high p-S6K1 expression render tumors sensitive to mTOR inhibition in vitro, these criteria were used to model tumor sensitivity. Overall, 26% of tumors (32/124) are predicted to be sensitive to mTOR inhibition, with variable rates for different tumors (melanoma 0% vs ovarian 41%). This is the first report on the PI3K/PTEN-AKT-mTOR pathway in common human tumors and evaluation of the coordinated expression of different signaling proteins. This study should provide a useful tool for selecting future targeted phase II and III clinical trials in the development of this exciting class of agents.
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PMID:Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human tumors. 1501 Aug 27

Cells that display chemokine receptors are capable of responding to a gradient of chemokine with a motility response that can translate into a chemotactic response. This continuous response to the chemokine sometimes requires that the chemokine receptor be internalized and recycled back to the membrane. We have shown that ligand activation of the CXC chemokine receptor, CXCR2, results in movement of the receptor into clathrin coated pits, followed by movement into the early endosome, the sorting endosome, then on to the recycling endosome prior to trafficking back into the plasma membrane compartment. Prolonged exposure to saturating concentrations of the ligand results in movement of a large percentage of the receptor into the late endosome and on to the lysosome for degradation. Mutation of the receptor in a manner which impairs receptor internalization by altering the binding of adaptor proteins AP-2 or beta arrestin to CXCR2, results in a marked reduction in the chemotactic response. Chemokine receptors also activate multiple intracellular signals that lead to the activation of the transcription factor, nuclear factor kappa beta (NF-kappaB). Transformation is often associated with a constitutive activation of NF-kappaB, leading to endogenous expression of chemokines and their receptors. This creates an autocrine loop with NF-kappaB in the activated state, and altered cxpression of factors that promote tumour angiogenesis and escape from apoptosis. We have shown that the constitutive activation of NF-kappaB in human melanoma tumours is accompanied by constitutive activation of the NF-kappaB inducing kinase (NIK) as well as the constitutive activation of AKT. As these factors that modulate the expression of anti-apoptotic factors work together, the tumour cells exhibit enhanced survival and growth. This never ending cycle of activation of NF-kappaB, leading to enhanced production of chemokines, enhanced activation of AKT and NF-kappaB, and enhanced transcription of inhibitors of apoptosis and chemokines, is one that has been used to foster the growth of the tumour to the disadvantage of the host. Thus we propose that blocking CXCR2 and/or NF-kappaB offers potential therapeutic promise for a number of chronic inflammatory conditions and cancers, including malignant melanoma.
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PMID:How do chemokine/chemokine receptor activations affect tumorigenesis? 1502 84

Arsenic is a well established human carcinogen and is associated with a variety of cancers including those of the skin. Paradoxically, arsenic has also been used, amid at low doses, in the treatment of leukemia for over a century. Here we demonstrate that low to moderate concentrations of arsenite (2-10 microm) that has little or no effect on normal melanocytes may induce apoptosis of human melanomas including highly metastatic ones despite their low surface Fas levels. The two prerequisites that dictate apoptotic response of melanomas upon arsenite treatment are low nuclear NF-kappaB activity and an endogenous expression of tumor necrosis factor alpha. Under these conditions, melanoma cells acquired sensitivity to tumor necrosis factor alpha-mediated killing. On the other hand, signaling pathways including those of phosphatidylinositol 3-kinase-AKT, MEK-ERK, and JNK play a protective role against arsenite-induced oxidative stress and apoptosis in melanoma cells. Suppression of these pathways dramatically accelerates arsenite-induced apoptosis. Taken together, these data could provide potential approaches to sensitize melanomas to the cytotoxic effects of arsenite through modulating the signaling pathways.
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PMID:Arsenite sensitizes human melanomas to apoptosis via tumor necrosis factor alpha-mediated pathway. 1502 28

Melanocytes are cells of the epidermis that synthesize melanin, which is responsible for skin pigmentation. Transformation of melanocytes leads to melanoma, a highly aggressive neoplasm, which displays resistance to apoptosis. In this report, we demonstrate that TNF-related apoptosis-inducing ligand (TRAIL), which was thought to kill only transformed cells, promotes very efficiently apoptosis of primary human melanocytes, leading to activation of caspases 8, 9 and 3, and the cleavage of vital proteins. Further, we show that stem cell factor (SCF), a physiologic melanocyte growth factor that activates both the phosphatidyl-inositol-3 kinase (PI3K) and the extracellular regulated kinase (ERK) pathways, strongly protects melanocytes from TRAIL and staurosporine killing. Interestingly, inhibition of PI3K or its downstream target AKT completely blocks the antiapoptotic effect of SCF, while inhibition of ERK has only a moderate effect. Our data indicate that protection evoked by SCF/PI3K/AKT cascade is not mediated by an increase in the intracellular level of FLIP. Further, only a sustained PI3K activity can protect melanocytes from apoptosis, thereby indicating that the PI3K/AKT pathway plays a pivotal role in melanocyte survival. The results gathered in this report bring new information on the molecular mechanisms involved in primary melanocyte apoptosis and survival that would help to better understand the process by which melanomas acquire their resistance to apoptosis.
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PMID:PI3K mediates protection against TRAIL-induced apoptosis in primary human melanocytes. 1524 84

Immunosuppressive factors, such as vascular endothelial growth factor, transforming growth factor-beta, prostaglandin E2, interleukin (IL)-10, and IL-6, are made frequently by cancer cells. These factors, along with others, can inhibit the development and function of tumor-reactive effector T cells and the clinical results of cancer vaccines. Production of these factors by tumor cells is associated with disease progression and may represent an active immune surveillance escape mechanism. However, a number of factors appear to be made directly in response to signaling molecules, such as RAS, AKT, and signal transducer and activator of transcription 3, which are activated as a result of genetic events that occur during oncogenesis. Methods to overcome the negative effects of immunosuppressive factors, which are "hard wired" into gene programs of cancer cells, might then improve the results of cancer vaccines. For example, specific blocking antibodies, which recognize such factors, or kinase inhibitors, which block the signaling pathways that lead to their production, could potentially be used as vaccine adjuvants. The effects of immunosuppressive factors may also be "turned off" by cytokines with tumor suppressor properties. The enhanced clinical and immunological effects of melanoma vaccines observed after the administration of high doses of interferon-alpha2b provide a "proof of principle" in human patients, that agents which counter the gene programs of cancer cells, causing them to intrinsically resist tumor-reactive T cells, may improve significantly the efficacy of cancer vaccines.
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PMID:Amplifying cancer vaccine responses by modifying pathogenic gene programs in tumor cells. 1527 80


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