microRNA-21-induced dissociation of PDCD4 from rictor contributes to Akt-IKKß-mTORC1 axis to regulate renal cancer cell invasion.
Exp Cell Res
; 328(1): 99-117, 2014 Oct 15.
Article
em En
| MEDLINE
| ID: mdl-25016284
ABSTRACT
Renal cancer metastasis may result from oncogenic forces that contribute to the primary tumor. We have recently identified microRNA-21 as an oncogenic driver of renal cancer cells. The mechanism by which miR-21 controls renal cancer cell invasion is poorly understood. We show that miR-21 directly downregulates the proapoptotic protein PDCD4 to increase migration and invasion of ACHN and 786-O renal cancer cells as a result of phosphorylation/activation of Akt and IKKß, which activate NFκB-dependent transcription. Constitutively active (CA) Akt or CA IKKß blocks PDCD4-mediated inhibition and restores renal cancer cell migration and invasion. PDCD4 inhibits mTORC1 activity, which was reversed by CA IKKß. Moreover, CA mTORC1 restores cell migration and invasion inhibited by PDCD4 and dominant negative IKKß. Moreover, PDCD4 negatively regulates mTORC2-dependent Akt phosphorylation upstream of this cascade. We show that PDCD4 forms a complex with rictor, an exclusive component of mTORC2, and that this complex formation is reduced in renal cancer cells due to increased miR-21 expression resulting in enhanced phosphorylation of Akt. Thus our results identify a previously unrecognized signaling node where high miR-21 levels reduce rictor-PDCD4 interaction to increase phosphorylation of Akt and contribute to metastatic fitness of renal cancer cells.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma de Células Renais
/
Proteínas de Transporte
/
Proteínas de Ligação a RNA
/
MicroRNAs
/
Complexos Multiproteicos
/
Quinase I-kappa B
/
Proteínas Proto-Oncogênicas c-akt
/
Proteínas Reguladoras de Apoptose
/
Serina-Treonina Quinases TOR
/
Túbulos Renais
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Exp Cell Res
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos