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Originally published In Press as doi:10.1074/jbc.M009256200 on February 7, 2001

J. Biol. Chem., Vol. 276, Issue 19, 16411-16417, May 11, 2001
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Modification of Alternative Splicing of Bcl-x Pre-mRNA in Prostate and Breast Cancer Cells
ANALYSIS OF APOPTOSIS AND CELL DEATH*

Danielle R. MercatanteDagger , Carl D. Bortner§, John A. Cidlowski§, and Ryszard KoleDagger

From the Dagger  Lineberger Comprehensive Cancer Center and the Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599-7295 and the § Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

There is ample evidence that deregulation of apoptosis results in the development, progression, and/or maintenance of cancer. Since many apoptotic regulatory genes (e.g. bcl-x) code for alternatively spliced protein variants with opposing functions, the manipulation of alternative splicing presents a unique way of regulating the apoptotic response. Here we have targeted oligonucleotides antisense to the 5'-splice site of bcl-xL, an anti-apoptotic gene that is overexpressed in various cancers, and shifted the splicing pattern of Bcl-x pre-mRNA from Bcl-xL to Bcl-xS, a pro-apoptotic splice variant. This approach induced significant apoptosis in PC-3 prostate cancer cells. In contrast, the same oligonucleotide treatment elicited a much weaker apoptotic response in MCF-7 breast cancer cells. Moreover, although the shift in Bcl-x pre-mRNA splicing inhibited colony formation in both cell lines, this effect was much less pronounced in MCF-7 cells. These differences in responses to oligonucleotide treatment were analyzed in the context of expression of Bcl-xL, Bcl-xS, and Bcl-2 proteins. The results indicate that despite the presence of Bcl-x pre-mRNA in a number of cell types, the effects of modification of its splicing by antisense oligonucleotides vary depending on the expression profile of the treated cells.

* This work was supported in part by Grants PO1-59299 and HL-51940-05 from the National Institutes of Health (to R. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence and reprint requests should be addressed: Lineberger Comprehensive Cancer Center, CB 7295, University of North Carolina, Chapel Hill, NC 27599-7295. Tel.: 919-966-1143; Fax: 919-966-3015; E-mail: kole@med.unc.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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