Sorafenib induces apoptosis in HL60 cells by inhibiting Src kinase-mediated STAT3 phosphorylation.
Anticancer Drugs
; 22(1): 79-88, 2011 Jan.
Article
em En
| MEDLINE
| ID: mdl-20881478
ABSTRACT
Signal transducer and activator of transcription 3 (STAT3) is constitutively active in approximately 50% of acute myeloid leukemia (AML) cases and mediates multiple cellular processes including cell resistance to apoptosis. Inhibition of constitutively active STAT3 has been shown to induce AML cell apoptosis. Our aim was to ascertain if sorafenib, a multikinase inhibitor, may also inhibit STAT3 signaling and, therefore, be efficacious for AML. We found that sorafenib inhibited proliferation and induced apoptosis in human AML cell line (HL60) cells. In addition, sorafenib exposure reduced constitutive STAT3 phosphorylation in HL60 cells and repressed STAT3 DNA-binding activity and Mcl-1 and Bcl-2 expression. Similar results were obtained with the Src kinase inhibitor I, suggesting that sorafenib suppresses STAT3 phosphorylation by inhibiting Src-kinase activity. Furthermore, significant inhibition of Src kinase activity by sorafenib was observed in the kinase assay. In addition, Src could be co-immunoprecipitated with STAT3, and the phosphorylation of STAT3 was significantly inhibited by sorafenib only in cell lines in which phosphorylated Src is highly expressed. Taken together, our study indicates that sorafenib blocks Src kinase-mediated STAT3 phosphorylation and decreases the expression of apoptosis regulatory proteins Mcl-1 and Bcl-2, which are associated with increased apoptosis in HL60 cells. These findings provide a rationale for the treatment of human AML.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Benzenossulfonatos
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Apoptose
/
Quinases da Família src
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Inibidores de Proteínas Quinases
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Fator de Transcrição STAT3
Limite:
Humans
Idioma:
En
Revista:
Anticancer Drugs
Assunto da revista:
ANTINEOPLASICOS
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
China