The AMPK stress response pathway mediates anoikis resistance through inhibition of mTOR and suppression of protein synthesis.
Cell Death Differ
; 19(3): 501-10, 2012 Mar.
Article
em En
| MEDLINE
| ID: mdl-21941369
ABSTRACT
Suppression of anoikis after detachment of cancer cells from the extracellular matrix is a key step during metastasis. Here we show that, after detachment, mouse embryonic fibroblasts (MEFs) transformed by K-Ras(V12) or ETV6-NTRK3 (EN) activate a transcriptional response overrepresented by genes related to bioenergetic stress and the AMP-activated protein kinase (AMPK) energy-sensing pathway. Accordingly, AMPK is activated in both transformed and non-transformed cells after detachment, and AMPK deficiency restores anoikis to transformed MEFs. However, AMPK activation represses the mTOR complex-1 (mTORC1) pathway only in transformed cells, suggesting a key role for AMPK-mediated mTORC1 inhibition in the suppression of anoikis. Consistent with this, AMPK-/- MEFs transformed by EN or K-Ras show sustained mTORC1 activation after detachment and fail to suppress anoikis. Transformed TSC1-/- MEFs, which are incapable of suppressing mTORC1, also undergo anoikis after detachment, which is reversed by mTORC1 inhibitors. Furthermore, transformed AMPK-/- and TSC1-/- MEFs both have higher total protein synthesis rates than wild-type controls, and translation inhibition using cycloheximide partially restores their anoikis resistance, indicating a mechanism whereby mTORC1 inhibition suppresses anoikis. Finally, breast carcinoma cell lines show similar detachment-induced AMPK/mTORC1 activation and restoration of anoikis by AMPK inhibition. Our data implicate AMPK-mediated mTORC1 inhibition and suppression of protein synthesis as a means for bioenergetic conservation during detachment, thus promoting anoikis resistance.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Biossíntese de Proteínas
/
Anoikis
/
Embrião de Mamíferos
/
Proteínas Quinases Ativadas por AMP
/
Serina-Treonina Quinases TOR
/
Fibroblastos
Limite:
Animals
Idioma:
En
Revista:
Cell Death Differ
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Canadá