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)

Prostate cancer is the second leading cause of cancer-related deaths in men. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. In the course of modeling malignant melanoma in a tyrosinase promoter transgenic system, we developed a genetically-engineered mouse (GEM) model of invasive prostate cancers, whereby an activating mutation of BRAF(V600E)--a mutation found in approximately 10% of human prostate tumors--was targeted to the epithelial compartment of the prostate gland on the background of Ink4a/Arf deficiency. These GEM mice developed prostate gland hyperplasia with progression to rapidly growing invasive adenocarcinoma without evidence of AKT activation, providing genetic proof that activation of MAP kinase signaling is sufficient to drive prostate tumorigenesis. Importantly, genetic extinction of BRAF(V600E) in established prostate tumors did not lead to tumor regression, indicating that while sufficient to initiate development of invasive prostate adenocarcinoma, BRAF(V600E) is not required for its maintenance.
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PMID:BRAF activation initiates but does not maintain invasive prostate adenocarcinoma. 1907 9

The AKT/PKB pathway plays a central role in tumor development and progression and is often up-regulated in different tumor types, including melanomas. We have recently reported on the in silico approach to identify putative inhibitors for AKT/PKB. Of the reported hits, we selected BI-69A11, a compound which was shown to inhibit AKT activity in in vitro kinase assays. Analysis of BI-69A11 was performed in melanoma cells, a tumor type that commonly exhibits up-regulation of AKT. Treatment of the UACC903 human melanoma cells, harboring the PTEN mutation, with BI-69A11 caused efficient inhibition of AKT S473 phosphorylation with concomitant inhibition of AKT phosphorylation of PRAS40. Treatment of melanoma cells with BI-69A11 also reduced AKT protein expression, which coincided with inhibition of AKT association with HSP-90. BI-69A11 treatment not only caused cell death of melanoma, but also prostate tumor cell lines. Notably, the effect of BI-69A11 on cell death was more pronounced in cells that express an active form of AKT. Significantly, intra-peritoneal injection of BI-69A11 caused effective regression of melanoma tumor xenografts, which coincided with elevated levels of cell death. These findings identify BI-69A11 as a potent inhibitor of AKT that is capable of eliciting effective regression of xenograft melanoma tumors.
Pigment Cell Melanoma Res 2009 Apr
PMID:BI-69A11-mediated inhibition of AKT leads to effective regression of xenograft melanoma. 1917 24

Signaling through the Tie2 receptor on endothelial cells has been shown to play an important role in normal and pathologic vascular development. We generated K1735 murine melanoma tumor cells that inducibly express soluble Tie2 receptor (Tie2Ex) to study the effects of inhibiting Tie2 signaling on tumor vasculature. Tie2Ex induction rapidly decreased AKT activation but not extracellular signal-regulated kinase (ERK) activation in tumor endothelial cells as detected by immunostaining. This was accompanied by an increase in endothelial cell TUNEL staining but no change in Ki-67 expression. Together with a decrease in the percentage of perfused vessels, this suggested that tumor vessel regression and impaired vascular function rather than angiogenesis inhibition was responsible for the delay in tumor growth following Tie2Ex treatment. However, Tie2Ex failed to inhibit the growth of larger, more established K1735 tumors. These tumors were additionally treated with sorafenib, a multikinase inhibitor that inhibits tumor endothelial cell ERK activation but not AKT activation. Combining Tie2Ex and sorafenib decreased both endothelial cell AKT and ERK activation, decreased endothelial cell survival and proliferation, and significantly inhibited growth of the more established tumors. These studies indicate that activity of specific signaling pathways and prosurvival effects are brought about by Tie2 activation in tumor endothelial cells, and knowledge of the effects of Tie2 inhibition can lead to development of more effective therapeutic regimens for inhibiting tumor neovascularization.
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PMID:Tie2 in tumor endothelial signaling and survival: implications for antiangiogenic therapy. 1927 84

Several congenital syndromes caused by germline mutations in tumor suppressor genes predispose to the development of glial tumors. In the last few decades our knowledge about the molecular functions of these genes and the pathogenesis of hereditary tumor syndromes has greatly increased. The most common syndromes are the neurofibromatoses (type 1 and type 2) and the tuberous scleroses complex. There are interesting overlaps in the molecular pathogen-esis. Deregulation of Ras or downstream Ras pathways including MEK/ERK and AKT/ mTOR plays an important role in these three syndromes. Other rare syndromes include Li-Fraumeni, melanoma-astrocytoma, and Turcot syndrome involving cell cycle regulators and DNA repair genes. The genes and pathways involved in the pathogenesis of these syndromes also play an important role in the development of sporadic tumors. Therefore research on hereditary syndromes contributes substantially to our understanding of tumor formation.
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PMID:Hereditary tumor syndromes and gliomas. 1932 39

Skin cancer is the most common cancer in the United States. UV radiation in sunlight is the major environmental factor causing skin cancer development. PTEN (phosphatase and tensin homolog deleted on chromosome 10), a recently discovered tumor suppressor gene, is frequently mutated, deleted, or epigenetically silenced in various human cancers. PTEN negatively regulates the oncogenic phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways. PTEN is clearly a critical tumor suppressor for skin cancer in humans and in mice. This review summarizes the recent progress in the function of PTEN in the development of skin cancer, including basal-cell carcinoma, squamous-cell carcinoma, and melanoma. The regulation of PTEN by UV radiation is also discussed in association with skin carcinogenesis. Understanding the fundamental mechanisms that lead to the reduction of PTEN function in skin carcinogenesis and the essential association with UV radiation opens up new opportunities for molecular chemoprevention and therapy of skin cancer by targeting PTEN pathways.
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PMID:PTEN: new insights into its regulation and function in skin cancer. 1934 9

Epidemiological and experimental evidence has supported the notion that solar ultraviolet (UV) radiation is the leading cause of skin cell damage and skin cancer. Non-melanoma skin cancer, one of the malignancies with the most rapidly increasing incidence, is suggested to be directly related to the total exposure to solar UV light. Over the past few years, the mechanisms of cellular responses to UV radiation have received unprecedented attention. Understanding how skin cells respond to UV radiation will undoubtedly help decipher what goes wrong in a variety of clinical skin disorders including skin cancer and will facilitate the development of novel therapeutic strategies. In the past decade, studies have established that UV radiation induces multifarious signal transduction pathways, some of which lead to apoptotic cell death, while others protect against this process. In this review, we summarize some of the most recent progresses regarding the involvement of multiple signal pathways in UV radiation-induced apoptosis in skin cells, especially in keratinocytes. These pathways include pro-apoptosis components such as MAPK, AMPK, and p53 as well as pro-survival components, namely, AKT and mTORC complexes.
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PMID:Parameters of protection against ultraviolet radiation-induced skin cell damage. 1936 Jul 45

Melanoma is highly resistant to chemotherapy. In melanoma, the PI3K-AKT-mTOR signaling pathway is constitutively activated through multiple mechanisms. Several experimental studies suggest that targeting the PI3K-AKT-mTOR signaling pathway is a promising strategy to overcome chemoresistance. This is the first report describing a chemosensitizing effect of mTOR inhibition in patients with melanoma. We report two cases of patients with metastatic melanoma who showed significant remission after combination of carboplatin and paclitaxel with the mTOR inhibitor sirolimus. Our case report, together with the literature discussed, suggests that mTOR inhibition possibly enhances the sensitivity of melanoma cells to chemotherapy and should prompt in-depth and clinical investigation.
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PMID:Significant response after treatment with the mTOR inhibitor sirolimus in combination with carboplatin and paclitaxel in metastatic melanoma patients. 1938 29

Melanoma is the deadliest form of skin cancer without an effective treatment. An understanding of the genetic basis of melanoma has recently shed light on some of the mechanisms of melanomagenesis. This review explores the major genes involved in familial and sporadic cutaneous melanoma with an emphasis on CDKN2A, CDK4, MC1R, and MAPK pathway targets (e.g., RAS and BRAF), apoptosis regulators (e.g., BCL-2, AKT, and APAF-1), and the tumor-suppressor genes TP53 and PTEN. New directions for therapeutics based on our current knowledge of the genes implicated in melanoma are also discussed.
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PMID:Molecular pathogenesis of cutaneous melanocytic neoplasms. 1940 Jun 96

Malignant melanoma is an aggressive tumor of the skin with a poor prognosis for patients with advanced disease. It is resistant to current therapeutic approaches. In melanoma, both the Ras/Raf/MEK/ERK (MAPK) and the PI3K/AKT (AKT) signalling pathways are constitutively activated through multiple mechanisms. Mutations of BRAF have been proposed to contribute to melanoma development. Increased activity of the MAPK pathway prevents apoptosis and induces cell cycle progression. PTEN deletion results in Akt activation. Akt activation can result in the phosphorylation and inactivation of Raf. This decrease in downstream MEK and ERK activation may lead to loss of differentiation or senescence. This review summarizes the most relevant studies focused on the signalling pathways involved in melanomagenesis. New therapeutic strategies are also reported.
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PMID:Melanoma: molecular pathogenesis and emerging target therapies (Review). 1942 65

The phosphatase and tensin homolog (PTEN) exerts its function, in part, by negatively regulating the well-known phosphatidylinositol-3-kinase/AKT signaling pathway. Previous histological work has suggested that alterations in the nuclear/cytoplasmic compartmentalization of PTEN may play a role in the development and progression of melanoma. In this study, we examined the nuclear/cytoplasmic compartmentalization of PTEN in melanoma cell lines and its correlation with the cell cycle. Studies were performed in melanoma cells lines using classic cell biological techniques. In contrast to breast cancer cell lines, we found that increased levels of nuclear PTEN levels correlate with G2 rather than with G1 arrest. In WM164 and SKmel28 cells, overexpression of PTEN protein did not significantly increase the number of cells in the G2 phase. Differential CDC2 phosphorylation levels in cells that overexpressed PTEN compared with those where PTEN was downregulated suggest some involvement of PTEN in G2 checkpoint regulation. The data suggest that although nuclear PTEN levels correlate with the G2 phase, the role of PTEN in modulating G2/M arrest is not limiting. Further, the specific cell cycle phase regulated by nuclear PTEN is cell-type dependent. Taken together, our observations suggest that in melanoma, nuclear PTEN is involved in G2 progression possibly through the modulation of CDC2, opening up a new arena for investigation.
Melanoma Res 2009 Aug
PMID:Nuclear PTEN levels and G2 progression in melanoma cells. 1947 84


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