Targeting the deregulated spliceosome core machinery in cancer cells triggers mTOR blockade and autophagy

Virginie Quidville, Samar Alsafadi, Aïcha Goubar, Frederic Commo, Veronique Scott, Catherine Pioche-Durieu, Isabelle Girault, Sonia Baconnais, Eric Le Cam, Vladimir Lazar, Suzette Delaloge, Mahasti Saghatchian, Patricia Pautier, Philippe Morice, Philippe Dessen, Stephan Vagner, Fabrice Andre

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    77 Citations (Scopus)

    Résumé

    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.

    langue originaleAnglais
    Pages (de - à)2247-2258
    Nombre de pages12
    journalCancer Research
    Volume73
    Numéro de publication7
    Les DOIs
    étatPublié - 1 avr. 2013

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