TRIGGERS

Abstract

: Targeting the deregulated spliceosome core machinery in cancer cells mTOR blockade and autophagy 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 to benign lesions, and could also define a subset of highly aggressive breast cancers. Small interfering RNA (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 non malignant 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 targetting spliceosome core components in oncology. cancer cell death increase in mRNA protein conversion. SKBr-3 cells were transfected with SNRPE, SNRPD1 siRNA or non-targeting control siRNA, then whole cell protein lysates were immunoblotted with LC3B, SNRPE, SNRPD1 and β -actin antibodies. to and