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]
日期:2013-01-29
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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