Targeting the deregulated spliceosome core machinery in cancer cells triggers mTOR blockade and autophagy.
Cancer Res
; 73(7): 2247-58, 2013 Apr 01.
Article
en En
| MEDLINE
| ID: mdl-23358685
The spliceosome is a large ribonucleoprotein complex that guides pre-mRNA splicing in eukaryotic cells. Here, we determine whether the spliceosome could constitute an attractive therapeutic target in cancer. Analysis of gene expression arrays from lung, breast, and ovarian cancers datasets revealed that several genes encoding components of the core spliceosome composed of a heteroheptameric Sm complex were overexpressed in malignant disease as compared with benign lesions and could also define a subset of highly aggressive breast cancers. siRNA-mediated depletion of SmE (SNRPE) or SmD1 (SNRPD1) led to a marked reduction of cell viability in breast, lung, and melanoma cancer cell lines, whereas it had little effect on the survival of the nonmalignant MCF-10A breast epithelial cells. SNRPE or SNRPD1 depletion did not lead to apoptotic cell death but autophagy, another form of cell death. Indeed, induction of autophagy was revealed by cytoplasmic accumulation of autophagic vacuoles and by an increase in both LC3 (MAP1LC3A) protein conversion and the amount of acidic autophagic vacuoles. Knockdown of SNRPE dramatically decreased mTOR mRNA and protein levels and was accompanied by a deregulation of the mTOR pathway, which, in part, explains the SNRPE-dependent induction of autophagy. These findings provide a rational to develop new therapeutic agents targeting spliceosome core components in oncology.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Autofagia
/
Neoplasias de la Mama
/
Empalmosomas
/
Proteínas Nucleares snRNP
/
Serina-Treonina Quinasas TOR
/
Neoplasias Pulmonares
/
Melanoma
Límite:
Female
/
Humans
Idioma:
En
Revista:
Cancer Res
Año:
2013
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Estados Unidos