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Research Articles: Therapeutics, Targets, and Development

Anticancer drugs affect the alternative splicing of Bcl-x and other human apoptotic genes

RNA Group, ¹ Département de Microbiologie et d'Infectiologie and ² Laboratoire de Génomique Fonctionnelle, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada

Requests for reprints: Benoit Chabot, Département de Microbiologie et d'Infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, Quebec, Canada J1H 5N4. Phone 819-564-5295; Fax: 819-564-5392. E-mail: Benoit.Chabot{at}USherbrooke.ca

Abstract

Inducing an apoptotic response is the goal of most current chemotherapeutic interventions against cancer. However, little is known about the effect of chemotherapeutic agents on the alternative splicing of apoptotic genes. Here, we have tested 20 of the mainstream anticancer drugs for their ability to influence the production of Bcl-x splice isoforms. We find that many drugs shift splicing toward the proapoptotic Bcl-x_S splice variant in 293 cells. The drugs modulate splicing decisions most likely through signaling events because the splicing switch is not compromised by inhibiting de novo protein synthesis or the activity of caspases. Several drugs also shift Bcl-x splicing in cancer cell lines (MCF-7, HeLa, PC-3, PA-1, and SKOV-3), but the set of active drugs varies between cell lines. We also examined the effect of anticancer agents on the alternative splicing of 95 other human apoptotic genes in different cell lines. Almost every drug can alter a subset of alternative splicing events in each cell line. Although drugs of the same class often influence the alternative splicing of the same units in individual cell lines, these units differ considerably between cell lines, indicating cell line–specific differences in the pathways that control splicing. [Mol Cancer Ther 2008;7(6):1398–409]

Grant support: Canadian Institute of Health Research (B. Chabot) and Genome Canada and Genome Québec.

Note: S.A. Elela is Chercheur Boursier Senior of the Fonds de la recherche en santé du Québec. B. Chabot is a Canada Research Chair in Functional Genomics.

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.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 2/26/08; revised 4/10/08; accepted 4/15/08.