A novel cyclinE/cyclinA-CDK inhibitor targets p27(Kip1) degradation, cell cycle progression and cell survival: implications in cancer therapy.
Cancer Lett
; 333(1): 103-12, 2013 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-23354589
ABSTRACT
p27(Kip1) (p27) binds and inhibits the cyclin E- or cyclin A-associated cyclin-dependent kinases (CDKs)2 and other CDKs, and negatively regulates G1-G2 cell cycle progression. To develop specific CDK inhibitors, we have modeled the interaction between p27 and cyclin A-CDK2, and designed a novel compound that mimics p27 binding to cyclin A-CDK2. The chemically synthesized inhibitor exhibited high potency and selective inhibition towards cyclin E/cyclin A-CDK2 kinase in vitro but not other kinases. To facilitate permeability of the inhibitor, a cell penetrating peptide (CPP) was conjugated to the inhibitor to examine its effect in several cancer cell lines. The CPP-conjugated inhibitor significantly inhibited the proliferation of cancer cells. The treatment of the inhibitor resulted in the increased accumulation of p27 and p21(Cip1/Waf1) (p21) and hypo-phosphorylation of retinoblastoma protein (Rb). The degradation of p27, mediated through the phosphorylation of threonine-187 in p27, was also inhibited. Consequently, exposure of cells to the inhibitor caused cell cycle arrest and apoptosis. We conclude that specific cyclinE/cyclin A-CDK2 inhibitors can be developed based on the interaction between p27 and cyclin/CDK to block cell cycle progression to prevent tumor growth and survival.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Prevencao_e_fatores_de_risco
/
Agentes_cancerigenos
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Tipos_de_cancer
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Outros_tipos
Base de dados:
MEDLINE
Assunto principal:
Ciclina A
/
Ciclina E
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Quinase 2 Dependente de Ciclina
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Inibidor de Quinase Dependente de Ciclina p27
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Cancer Lett
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
China