Identification of ras-related nuclear protein, targeting protein for xenopus kinesin-like protein 2, and stearoyl-coa desaturase 1 as promising cancer targets from an RNAi-based screen

To identify new candidate cancer drug targets, we used RNAi as a tool to functionally evaluate genes that play a role in maintaining human tumor cell survival. We screened a small interfering RNA (siRNA) library directed against approximately 3,700 individual genes to assess the ability of siRNAs to...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2007-05, Vol.67 (9), p.4390-4398
Main Authors: MORGAN-LAPPE, Susan E, TUCKER, Lora A, XIAOLI HUANG, QIAN ZHANG, SARTHY, Aparna V, ZAKULA, Dorothy, VERNETTI, Lawrence, SCHURDAK, Mark, JIEYI WANG, FESIK, Stephen W
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Cell Cycle - genetics
Cell Cycle Proteins - genetics
Cell Death - genetics
Cell Line, Tumor
Cell Survival - genetics
Gene Library
Genes, ras
Humans
Medical sciences
Microtubule-Associated Proteins - genetics
Neoplasm Proteins - genetics
Neoplasms - genetics
Neoplasms - pathology
Nuclear Proteins - genetics
Pharmacology. Drug treatments
Phosphoproteins - genetics
ran GTP-Binding Protein - genetics
RNA Interference
RNA, Small Interfering - genetics
Stearoyl-CoA Desaturase - genetics
Tumors
Xenopus
Xenopus Proteins - genetics
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Summary:To identify new candidate cancer drug targets, we used RNAi as a tool to functionally evaluate genes that play a role in maintaining human tumor cell survival. We screened a small interfering RNA (siRNA) library directed against approximately 3,700 individual genes to assess the ability of siRNAs to induce cell death in an in vitro cell cytotoxicity assay. We found that siRNAs specifically targeting ras-related nuclear protein (Ran), targeting protein for Xenopus kinesin-like protein 2 (TPX2), and stearoyl-CoA desaturase 1 (SCD1), significantly reduced the survival of multiple human tumor cell lines. Further target validation studies revealed that treatment with Ran and TPX2 siRNAs differentially reduced the survival of activated K-Ras-transformed cells compared with their normal isogenic counterparts in which the mutant K-Ras gene had been disrupted (DKS-8). Knockdown of Ran and TPX2 in activated mutant K-Ras cells selectively induced S-phase arrest or transient G(2)-M arrest phenotypes, respectively, that preceded apoptotic cell death. Given our observations that Ran and TPX2 depletion preferentially reduces the survival of activated K-Ras-transformed cells, these two proteins may serve as useful anticancer targets in tumors expressing the activated K-Ras oncogene.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-06-4132