title: The cellular apoptosis susceptibility CAS/CSE1L gene protects ovarian cancer cells from death by suppressing RASSF1C.
abstract: The cellular apoptosis susceptibility gene CAS/CSE1L is overexpressed in cancer, although it was originally identified as a gene that renders cells vulnerable to apoptotic stimuli. CAS/CSE1L has roles in the nucleocytoplasmic recycling of importin-α and in the regulation of gene expression, cell migration, and secretion. We identified CAS/CSE1L as a survival factor for ovarian cancer cells in vitro and in vivo. In 3/3 ovarian cancer cell lines, CAS/CSE1L was down-modulated by the unorthodox proapoptotic signaling of the MET receptor. CAS/CSE1L knockdown with RNA interference committed the ovarian cancer cells to death, but not immortalized normal cells and breast and colon cancer cells. In 70 and 95% of these latter cells, respectively, CAS/CSE1L was localized in the cytoplasm, while it accumulated in the nucleus in >90% of ovarian cancer cells. Nuclear localization depended on AKT, which was constitutively active in ovarian cancer cells. In the nucleus, CAS/CSE1L regulated the expression of the proapoptotic Ras-association domain family 1 gene products RASSF1C and RASSF1A, which mediated death signals evoked by depletion of CAS/CSE1L. Our data show that CAS/CSE1L protects ovarian cancer cells from death through transcriptional suppression of a proapoptotic gene and suggest that the localization of CAS/CSE1L dictates its function.
authors.affiliation: Department of Oncological Sciences, University of Torino School of Medicine, Turin, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Lorenzato
authors.forename: Cosimo
authors.initials: C
authors.lastname: Martino
authors.forename: Nadia
authors.initials: N
authors.lastname: Dani
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Oligschläger
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Ferrero
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Biglia
authors.forename: Raffaele
authors.initials: R
authors.lastname: Calogero
authors.forename: Martina
authors.initials: M
authors.lastname: Olivero
authors.forename: Maria Flavia
authors.initials: MF
authors.lastname: Di Renzo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D029563:Cellular Apoptosis Susceptibility Protein / Q000235:genetics*; D002945:Cisplatin / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000187:drug effects*; D015854:Up-Regulation
chemical_list: D029563:Cellular Apoptosis Susceptibility Protein; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D017228:Hepatocyte Growth Factor; D002945:Cisplatin