This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morgan-Lappe, S. E. Articles by Fesik, S. W. Search for Related Content PubMed PubMed Citation Articles by Morgan-Lappe, S. E. Articles by Fesik, S. W.

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

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

Requests for reprints: Susan E. Morgan-Lappe, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064. Phone: 847-937-6432; Fax: 847-938-1336; E-mail: susan.morgan-lappe{at}abbott.com or Stephen W. Fesik, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064. Phone: 847-937-1201; E-mail: stephen.fesik{at}abbott.com.

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 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 G₂-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. [Cancer Res 2007;67(9):4390–7]

This article has been cited by other articles:

				G. Pascreau, F. Eckerdt, A. L. Lewellyn, C. Prigent, and J. L. Maller Phosphorylation of p53 Is Regulated by TPX2-Aurora A in Xenopus Oocytes J. Biol. Chem., February 27, 2009; 284(9): 5497 - 5505. [Abstract] [Full Text] [PDF]

				M. Zheng, S. E. Morgan-Lappe, J. Yang, K. M. Bockbrader, D. Pamarthy, D. Thomas, S. W. Fesik, and Y. Sun Growth Inhibition and Radiosensitization of Glioblastoma and Lung Cancer Cells by Small Interfering RNA Silencing of Tumor Necrosis Factor Receptor-Associated Factor 2 Cancer Res., September 15, 2008; 68(18): 7570 - 7578. [Abstract] [Full Text] [PDF]

				P. Kalab and R. Heald The RanGTP gradient - a GPS for the mitotic spindle J. Cell Sci., May 15, 2008; 121(10): 1577 - 1586. [Abstract] [Full Text] [PDF]

				F. Xia, C. W. Lee, and D. C. Altieri Tumor Cell Dependence on Ran-GTP-Directed Mitosis Cancer Res., March 15, 2008; 68(6): 1826 - 1833. [Abstract] [Full Text] [PDF]