title: Survivin depletion preferentially reduces the survival of activated K-Ras-transformed cells.
abstract: To identify cancer-specific targets, we have conducted a synthetic lethal screen using a small interfering RNA (siRNA) library targeting approximately 4,000 individual genes for enhanced killing in the DLD-1 colon carcinoma cell line that expresses an activated copy of the K-Ras oncogene. We found that siRNAs targeting baculoviral inhibitor of apoptosis repeat-containing 5 (survivin) significantly reduced the survival of activated K-Ras-transformed cells compared with its normal isogenic counterpart in which the mutant K-Ras gene had been disrupted (DKS-8). In addition, survivin siRNA induced a transient G(2)-M arrest and marked polyploidy that was associated with increased caspase-3 activation in the activated K-Ras cells. These results indicate that tumors expressing the activated K-Ras oncogene may be particularly sensitive to inhibitors of the survivin protein.
authors.affiliation: Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. aparna.sarthy@abbott.com
authors.forename: Aparna V
authors.initials: AV
authors.lastname: Sarthy
authors.forename: Susan E
authors.initials: SE
authors.lastname: Morgan-Lappe
authors.forename: Dorothy
authors.initials: D
authors.lastname: Zakula
authors.forename: Lawrence
authors.initials: L
authors.lastname: Vernetti
authors.forename: Mark
authors.initials: M
authors.lastname: Schurdak
authors.forename: Jeremy C L
authors.initials: JC
authors.lastname: Packer
authors.forename: Mark G
authors.initials: MG
authors.lastname: Anderson
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D000483:Alleles; D017209:Apoptosis; D016923:Cell Death; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002999:Clone Cells; D016195:G2 Phase; D052138:Genes, Neoplasm; D011905:Genes, ras; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000378:metabolism*; D008938:Mitosis; D050505:Mutant Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000378:metabolism*; D011123:Polyploidy; D034741:RNA, Small Interfering / Q000378:metabolism; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D050505:Mutant Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000077022:Survivin