Targeting the Deregulated Spliceosome Core Machinery in Cancer Cells Triggers mTOR Blockade and Autophagy

剪接体 自噬 PI3K/AKT/mTOR通路 癌症研究 生物 基因敲除 细胞生物学 小干扰RNA 程序性细胞死亡 癌症 RNA剪接 信号转导 细胞培养 细胞凋亡 核糖核酸 基因 遗传学
作者
Virginie Quidville,Samar Alsafadi,Aïcha Goubar,Frédéric Commo,Véronique Scott,Catherine Pioche‐Durieu,Isabelle Girault,Sonia Baconnais,Éric Le Cam,Vladimir Lazar,Suzette Delaloge,Mahasti Saghatchian,Patricia Pautier,Philippe Morice,P Dessen,Stéphan Vagner,Fabrice André
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:73 (7): 2247-2258 被引量:94
标识
DOI:10.1158/0008-5472.can-12-2501
摘要

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. Cancer Res; 73(7); 2247–58. ©2013 AACR.
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