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J. Biol. Chem., Vol. 277, Issue 51, 49374-49382, December 20, 2002
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From the Overexpression of Bcl-xL, an anti-apoptotic
member of the Bcl-2 family, negatively correlates with the
sensitivity of various cancers to chemotherapeutic agents. We show here
that high levels of expression of Bcl-xL promoted apoptosis of cells
treated with an antisense oligonucleotide (5'Bcl-x AS) that shifts the
splicing pattern of Bcl-x pre-mRNA from the anti-apoptotic variant,
Bcl-xL, to the pro-apoptotic variant, Bcl-xS. This surprising finding illustrates the advantage of antisense-induced modulation of
alternative splicing versus down-regulation of targeted
genes. It also suggests a specificity of the oligonucleotide effects
since non-cancerous cells with low levels of Bcl-xL should resist the
treatment. 5'Bcl-x AS sensitized cells to several antineoplastic agents
and radiation and was effective in promoting apoptosis of MCF-7/ADR
cells, a breast cancer cell line resistant to doxorubicin via
overexpression of the mdr1 gene. Efficacy of 5'Bcl-x AS
combined with chemotherapeutic agents in the PC3 prostate cancer cell
line may be translated to clinical prostate cancer since recurrent
prostate cancer tissue samples expressed higher levels of Bcl-xL than
benign prostate tissue. Treatment with 5'Bcl-x AS may enhance
the efficacy of standard anti-cancer regimens and should be explored,
especially in recurrent prostate cancer.
Cellular Response to an Antisense-mediated Shift of Bcl-x
Pre-mRNA Splicing and Antineoplastic Agents*
,¶
UNC Lineberger Comprehensive Cancer Center
and Departments of Pharmacology, § Surgery (Division of
Urology), and Pathology and Laboratory Medicine, University of North
Carolina, Chapel Hill, North Carolina 27599
*
This work was supported in part by Grants PO1-GM59299-01 (to
R. K.) and PO1-CA77739 (to J. L. M.) from the National Institutes of
Health.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.
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