Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
PLoS One ; 9(4): e92041, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24694787

RESUMO

Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited in vivo antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Célula de Merkel/tratamento farmacológico , Transformação Celular Viral/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Infecções por Polyomavirus/tratamento farmacológico , Polyomavirus/metabolismo , Infecções Tumorais por Vírus/tratamento farmacológico , Animais , Antígenos Virais de Tumores/genética , Antígenos Virais de Tumores/metabolismo , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/metabolismo , Carcinoma de Célula de Merkel/virologia , Linhagem Celular Tumoral , Transformação Celular Viral/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Choque Térmico HSP70/biossíntese , Proteínas de Choque Térmico HSP70/genética , Humanos , Camundongos , Camundongos Endogâmicos NOD , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Polyomavirus/genética , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/metabolismo , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/metabolismo , Infecções Tumorais por Vírus/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
PLoS One ; 7(2): e31255, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22363598

RESUMO

Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.


Assuntos
Carcinoma de Célula de Merkel/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/enzimologia , Antígenos Transformantes de Poliomavirus/metabolismo , Sequência de Bases , Carcinoma Basocelular/enzimologia , Carcinoma Basocelular/patologia , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/patologia , Linhagem Celular Tumoral , Cromonas/farmacologia , Análise Mutacional de DNA , Ativação Enzimática/efeitos dos fármacos , Humanos , Dados de Sequência Molecular , Morfolinas/farmacologia , Mutação/genética , Fosfatidilinositol 3-Quinases/genética , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação/efeitos dos fármacos , Fosfotreonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
3.
Int J Cancer ; 130(4): 847-56, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21413015

RESUMO

Merkel cell carcinoma (MCC) is a highly aggressive skin cancer that frequently harbours Merkel cell polyomavirus (MCV) DNA integrated in the genome of the tumor cells. In our study, we elaborate our recent finding that MCV-positive MCC cell lines require the expression of the viral T antigens (TA). Indeed, in a xeno-transplantation model, we prove that TA expression is essential also in an in vivo situation, as knock down of TA leads to tumor regression. Moreover, rescuing TA short hairpin RNA (shRNA)-treated MCV-positive MCC cells by ectopic expression of shRNA-insensitive TAs clearly demonstrates that the observed effect is caused by TA knockdown. Notably, introduction of a mutation in the LTA protein interfering with LTA binding to the retinoblastoma protein (RB) ablated this rescue. The importance of this interaction was further confirmed as LTA-specific knockdown leads to explicit cell growth inhibition. In summary, the presented data demonstrate that established MCV-positive MCC tumors critically depend on TA expression, in particular the LTA and RB interaction, for sustained tumor growth. Consequently, interference with LTA/RB interaction appears as promising strategy to treat MCC.


Assuntos
Antígenos Transformantes de Poliomavirus/fisiologia , Carcinoma de Célula de Merkel/patologia , Poliomavírus das Células de Merkel/imunologia , Proteína do Retinoblastoma/metabolismo , Neoplasias Cutâneas/patologia , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células , Doxiciclina/farmacologia , Humanos , Camundongos , Camundongos SCID , Fenótipo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...