RESUMO
AMP-activated protein kinase (AMPK) functions as an energy sensor and is pivotal in maintaining cellular metabolic homeostasis. Numerous studies have shown that down-regulation of AMPK kinase activity or protein stability not only lead to abnormality of metabolism but also contribute to tumor development. However, whether transcription regulation of AMPK plays a critical role in cancer metastasis remains unknown. In this study, we demonstrate that AMPKα1 expression is down-regulated in advanced human breast cancer and is associated with poor clinical outcomes. Transcription of AMPKα1 is inhibited on activation of PI3K and HER2 through ΔNp63α. Ablation of AMPKα1 expression or inhibition of AMPK kinase activity leads to disruption of E-cadherin-mediated cell-cell adhesion in vitro and increased tumor metastasis in vivo. Furthermore, restoration of AMPKα1 expression significantly rescues PI3K/HER2-induced disruption of cell-cell adhesion, cell invasion, and cancer metastasis. Together, these results demonstrate that the transcription control is another layer of AMPK regulation and suggest a critical role for AMPK in regulating cell-cell adhesion and cancer metastasis.
Assuntos
Proteínas Quinases Ativadas por AMP/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Linhagem Celular Tumoral , Cromonas/farmacologia , Intervalo Livre de Doença , Regulação para Baixo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Lapatinib/farmacologia , Camundongos , Morfolinas/farmacologia , Estadiamento de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Prognóstico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Análise Serial de Tecidos , Transcrição Gênica/efeitos dos fármacos , Ativação Transcricional , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Ketoconazole is a typical treatment available for pityriasis versicolor; tretinoin cream is effective, too. Adapalene gel is a tretinoin derivative and has a lower incidence of irritation compared with other topical retinoid products. However, there are no reports on adapalene gel for the treatment of pityriasis versicolor. OBJECTIVE: To study the effect of adapalene gel comparing the treatment with adapalene gel and 2% ketoconazole cream in pityriasis versicolor. METHODS: Eighty patients suffering from pityriasis versicolor were randomly divided into two groups; one group were treated with 2% ketoconazole cream topically twice daily for 2 weeks, adapalene gel was used for the other group in a similar fashion. RESULTS: There were no significant differences in efficacy between the two groups. No major side effects were noted in any of the groups either. CONCLUSION: Adapalene was the favorable option in the treatment of pityriasis versicolor. The probable therapeutic mechanism of adapalene is also discussed.