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Research Articles: Therapeutics, Targets, and Development

Survivin depletion preferentially reduces the survival of activated K-Ras-transformed cells

¹ Cancer Research and ² Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois; ³ Department of Cell Biology, School of Medicine, Fukuoka University, Fukuoka, Japan; and ⁴ Research Institute, International Medical Center of Japan, Tokyo, Japan

Requests for reprints: Aparna V. Sarthy, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064. Phone: 847-937-1571. Fax: 847-937-4007. E-mail: aparna.sarthy{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

Abstract

To identify cancer-specific targets, we have conducted a synthetic lethal screen using a small interfering RNA (siRNA) library targeting 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 G₂-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. [Mol Cancer Ther 2007;6(1):269–76]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: A.V. Sarthy and S.E. Morgan-Lappe contributed equally to this work.

Received 9/12/06; revised 10/24/06; accepted 11/22/06.

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