Survivin depletion preferentially reduces the survival of activated K-Ras-transformed cells.
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.
Sarthy
Aparna V
AV
Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. aparna.sarthy@abbott.com
Morgan-Lappe
Susan E
SE
Zakula
Dorothy
D
Vernetti
Lawrence
L
Schurdak
Mark
M
Packer
Jeremy C L
JC
Anderson
Mark G
MG
Shirasawa
Senji
S
Sasazuki
Takehiko
T
Fesik
Stephen W
SW
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
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