Targeting the deregulated spliceosome core machinery in cancer cells triggers mTOR blockade and autophagy.
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.
Institut National de la Santé et de la Recherche Médicale (INSERM) U981, Paris, France.
Virginie
V
Quidville
Samar
S
Alsafadi
Aïcha
A
Goubar
Frédéric
F
Commo
Véronique
V
Scott
Catherine
C
Pioche-Durieu
Isabelle
I
Girault
Sonia
S
Baconnais
Eric
E
Le Cam
Vladimir
V
Lazar
Suzette
S
Delaloge
Mahasti
M
Saghatchian
Patricia
P
Pautier
Philippe
P
Morice
Philippe
P
Dessen
Stéphan
S
Vagner
Fabrice
F
André
D017209:Apoptosis; D001343:Autophagy; D015153:Blotting, Western; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D017381:Spliceosomes / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055517:snRNP Core Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D034741:RNA, Small Interfering; C526409:SNRPD1 protein, human; C526413:SNRPE protein, human; D055517:snRNP Core Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases