Abstract

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.

Highlights

  • Targeted therapies have been shown to improve outcome in breast cancers

  • We evaluated the expression of 15 genes related to spliceosomal assembly, according to the BioCarta database, including U1snRNP-specific protein (SNRNP70 or U1-70K), constitutive splicing factors (U2AF1, U2AF2), splicing regulator (SFRS2), and core spliceosomal components (SNRP-A/A1, B/B2, C, D1/D2/ D3, E, F, and G)

  • We report that components of the Sm core spliceosomal machinery are overexpressed in cancer, regulate mTOR, and impact on cell proliferation and autophagy (Fig. 6E)

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Summary

Introduction

Targeted therapies have been shown to improve outcome in breast cancers. Molecular targeted agents usually inhibit key oncogenic pathways involved in cancer progression or resistance to conventional treatments. Most of these new molecular therapies target kinase pathways and are usually highly effective in a specific molecular segment. Accumulative evidence has been reported that beyond kinase and DNA repair defects, many pathways are crucial for cancer progression. Looking for novel pathways involved in cancer progression, we previously identified spliceosome assembly components as Authors' Affiliations: 1Institut National de la Sante et de la Recherche Medicale (INSERM) U981, Paris; 2Institut de cancerologie Gustave Roussy, Villejuif; and 3Universite Paris-Sud XI, Kremlin-Bice^tre, France

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