TY - JOUR
T1 - Targeting the deregulated spliceosome core machinery in cancer cells triggers mTOR blockade and autophagy
AU - Quidville, Virginie
AU - Alsafadi, Samar
AU - Goubar, Aïcha
AU - Commo, Frederic
AU - Scott, Veronique
AU - Pioche-Durieu, Catherine
AU - Girault, Isabelle
AU - Baconnais, Sonia
AU - Le Cam, Eric
AU - Lazar, Vladimir
AU - Delaloge, Suzette
AU - Saghatchian, Mahasti
AU - Pautier, Patricia
AU - Morice, Philippe
AU - Dessen, Philippe
AU - Vagner, Stephan
AU - Andre, Fabrice
PY - 2013/4/1
Y1 - 2013/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84876007868&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-12-2501
DO - 10.1158/0008-5472.CAN-12-2501
M3 - Article
AN - SCOPUS:84876007868
SN - 0008-5472
VL - 73
SP - 2247
EP - 2258
JO - Cancer Research
JF - Cancer Research
IS - 7
ER -