miR-491-5p-induced apoptosis in ovarian carcinoma depends on the direct inhibition of both BCL-XL and EGFR leading to BIM activation.
Cell Death Dis
; 5: e1445, 2014 Oct 09.
Article
en En
| MEDLINE
| ID: mdl-25299770
We sought to identify miRNAs that can efficiently induce apoptosis in ovarian cancer cells by overcoming BCL-X(L) and MCL1 anti-apoptotic activity, using combined computational and experimental approaches. We found that miR-491-5p efficiently induces apoptosis in IGROV1-R10 cells by directly inhibiting BCL-X(L) expression and by inducing BIM accumulation in its dephosphorylated form. This latter effect is due to direct targeting of epidermal growth factor receptor (EGFR) by miR-491-5p and consequent inhibition of downstream AKT and MAPK signalling pathways. Induction of apoptosis by miR-491-5p in this cell line is mimicked by a combination of EGFR inhibition together with a BH3-mimetic molecule. In contrast, SKOV3 cells treated with miR-491-5p maintain AKT and MAPK activity, do not induce BIM and do not undergo cell death despite BCL-XL and EGFR downregulation. In this cell line, sensitivity to miR-491-5p is restored by inhibition of both AKT and MAPK signalling pathways. Altogether, this work highlights the potential of miRNA functional studies to decipher cell signalling pathways or major regulatory hubs involved in cell survival to finally propose the rationale design of new strategies on the basis of pharmacological combinations.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Ováricas
/
Carcinoma
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Proteínas Proto-Oncogénicas
/
Apoptosis
/
MicroARNs
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Proteínas Reguladoras de la Apoptosis
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Proteína bcl-X
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Receptores ErbB
/
Proteínas de la Membrana
Tipo de estudio:
Prognostic_studies
Límite:
Female
/
Humans
Idioma:
En
Revista:
Cell Death Dis
Año:
2014
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Reino Unido