title: Identification of cell surface and secreted proteins essential for tumor cell survival using a genetic suppressor element screen.
abstract: Survival factors play critical roles in regulating cell growth in normal and cancer cells. We designed a genetic screen to identify survival factors which protect tumor cells from apoptosis. A retroviral expression library of random cDNA fragments was constructed from cancer cells and used to transduce the colon carcinoma cell line HCT116. Recipient cells were functionally selected for induction of caspase 3-mediated apoptosis. Analyses of over 10,000 putative genetic suppression elements (GSEs) sequences revealed cognate gene candidates that are implicated in apoptosis. We further analysed 26 genes encoding cell surface and secreted proteins that can potentially serve as targets for therapeutic antibodies. Tetracycline-inducible GSEs from several gene candidates induced apoptosis in stable HCT 116 cell lines. Similar phenotypes were caused by RNAi derived from the same genes. Our data suggest requirement for the cell surface targets IGF2R, L1CAM and SLC31A1 in tumor cell growth in vitro, and suggests that IGF2R is required for xenograft tumor growth in a mouse model.
authors.affiliation: PPD Discovery, Inc., 1505 O'Brien Drive, Menlo Park, CA 94025, USA.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Gelman
authors.forename: X Katherine
authors.initials: XK
authors.lastname: Ye
authors.forename: Robert
authors.initials: R
authors.lastname: Stull
authors.forename: David
authors.initials: D
authors.lastname: Suhy
authors.forename: Liang
authors.initials: L
authors.lastname: Jin
authors.forename: Dean
authors.initials: D
authors.lastname: Ng
authors.forename: Bruce
authors.initials: B
authors.lastname: Than
authors.forename: May
authors.initials: M
authors.lastname: Ji
authors.forename: Alison
authors.initials: A
authors.lastname: Pan
authors.forename: Paul
authors.initials: P
authors.lastname: Perez
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Patricia
authors.initials: P
authors.lastname: Yeung
authors.forename: Luz Maria
authors.initials: LM
authors.lastname: Garcia
authors.forename: Rachel
authors.initials: R
authors.lastname: Harte
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lamar
authors.forename: Roya
authors.initials: R
authors.lastname: Tavassoli
authors.forename: Scot
authors.initials: S
authors.lastname: Kennedy
authors.forename: Stephen
authors.initials: S
authors.lastname: Osborn
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Chin
authors.forename: Kay
authors.initials: K
authors.lastname: Meshaw
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Holzmayer
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Axenovich
authors.forename: Arie
authors.initials: A
authors.lastname: Abo
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000473:pathology*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000494:pharmacology; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous
chemical_list: D034741:RNA, Small Interfering; D017527:Receptor, IGF Type 2; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases