Sorafenib induces autophagic cell death and apoptosis in hepatic stellate cell through the JNK and Akt signaling pathways.
Anticancer Drugs
; 27(3): 192-203, 2016 Mar.
Article
em En
| MEDLINE
| ID: mdl-26629768
ABSTRACT
Increasing hepatic stellate cell (HSC) death is an attractive approach for limiting liver fibrosis. We investigated the molecular mechanisms underlying the effects of sorafenib on HSCs. LX2 cells were incubated with sorafenib and a variety of inhibitors of apoptosis, autophagy, and necrosis. Electron microscopy was used to observe autophagosomes. Inhibitors and siRNA were used to examine the role of the Akt/mTOR/p70S6K and JNK pathways. Ultrastructural analysis revealed that rat HSCs treated with 5 µmol/l sorafenib accumulated residual digested material and empty or autophagic vacuoles. Incubating LX2 cells with lysosomal protease inhibitors increased the accumulation of LC3-II, indicating that sorafenib enhances autophagic flux in HSCs. Autophagy may precede apoptosis. Lower concentrations of sorafenib and a shorter treatment time resulted in the dominance of autophagic cell death over apoptosis. Further analysis showed that Beclin 1 is inactivated by the caspases induced by sorafenib during apoptosis. Inhibition of autophagy in LX2 cells using 3-methyladenine treatment or siRNA-mediated knockdown of Atg5 resulted in a marked increase in apoptosis. Finally, sorafenib induced programmed cell death by attenuation and activation of Akt/mTOR/p70S6K and JNK signaling. Sorafenib-induced cell death is mediated by both autophagy and apoptosis. Elucidation of the signaling pathways activated by sorafenib could potentially lead to novel antifibrosis therapies for chronic liver diseases.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Compostos de Fenilureia
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Autofagia
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Proteínas Tirosina Quinases
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Apoptose
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Niacinamida
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Proteínas Quinases JNK Ativadas por Mitógeno
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Proteínas Proto-Oncogênicas c-akt
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Células Estreladas do Fígado
Limite:
Animals
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Humans
Idioma:
En
Revista:
Anticancer Drugs
Assunto da revista:
ANTINEOPLASICOS
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos