TY - JOUR
T1 - Enhancing TRAIL-induced apoptosis by Bcl-XL siRNA
AU - Zhu, Hongbo
AU - Guo, Wei
AU - Zhang, Lidong
AU - Davis, John J.
AU - Wu, Shuhong
AU - Teraishi, Fuminori
AU - Cao, Xiaobo
AU - Smythe, W. Roy
AU - Fang, Bingliang
N1 - Funding Information:
This article represents partial fulfillment of the requirements for the Ph.D. degree for J.J.D. This work was supported in part by grants from the National Cancer Institute (RO1 CA092487-01A1 and RO1 CA098582-01A1, to B.F.), and a Cancer Center Core Grant from the National Institutes of Health (CA16672).
PY - 2005/4
Y1 - 2005/4
N2 - We previously found that a change in the balance between mitochondrial pro- and anti-apoptotic proteins caused by ectopic expression of the Bax gene led to increased induction of apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). To investigate whether a similar effect can be elicited by down-regulating Bcl-XL, an anti-apoptotic protein, we tested the effects of a small interfering RNA (siRNA) specific for Bcl-X L in TRAIL-resistant cells. The down-regulation of Bcl-XL by siRNA inhibited cell proliferation and sensitized TRAIL-induced apoptosis in human cancer cells with both acquired and intrinsic TRAIL resistance. Combining the Bcl-XL siRNA with TRAIL protein treatment resulted in an increase in the percentage of apoptotic cells and increased cleavage of caspase-8, caspase-9, caspase-3, and PARP. Furthermore, the release of cytochrome c but not Smac from mitochondria was induced by Bcl-XL siRNA alone, and this release was dramatically amplified by combining the Bcl-XL siRNA and TRAIL protein treatment. Together, our data suggest that simultaneous triggering of the death receptor and mitochondrial apoptotic pathways leads to enhanced induction of apoptosis, which makes it potentially useful for the treatment of resistant cancers.
AB - We previously found that a change in the balance between mitochondrial pro- and anti-apoptotic proteins caused by ectopic expression of the Bax gene led to increased induction of apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). To investigate whether a similar effect can be elicited by down-regulating Bcl-XL, an anti-apoptotic protein, we tested the effects of a small interfering RNA (siRNA) specific for Bcl-X L in TRAIL-resistant cells. The down-regulation of Bcl-XL by siRNA inhibited cell proliferation and sensitized TRAIL-induced apoptosis in human cancer cells with both acquired and intrinsic TRAIL resistance. Combining the Bcl-XL siRNA with TRAIL protein treatment resulted in an increase in the percentage of apoptotic cells and increased cleavage of caspase-8, caspase-9, caspase-3, and PARP. Furthermore, the release of cytochrome c but not Smac from mitochondria was induced by Bcl-XL siRNA alone, and this release was dramatically amplified by combining the Bcl-XL siRNA and TRAIL protein treatment. Together, our data suggest that simultaneous triggering of the death receptor and mitochondrial apoptotic pathways leads to enhanced induction of apoptosis, which makes it potentially useful for the treatment of resistant cancers.
KW - Apoptosis
KW - Bcl-X
KW - Resistance
KW - Small interfering rna
KW - Tumor necrosis factor-related apoptosis-inducing ligand
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U2 - 10.4161/cbt.4.4.1616
DO - 10.4161/cbt.4.4.1616
M3 - Article
C2 - 15846108
AN - SCOPUS:25144453966
SN - 1538-4047
VL - 4
SP - 399
EP - 403
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 4
ER -
