共 41 条
Targeted therapy of the XIAP/proteasome pathway overcomes TRAIL-resistance in carcinoma by switching apoptosis signaling to a Bax/Bak-independent 'type I' mode
被引:41
作者:

Gillissen, B.
论文数: 0 引用数: 0
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机构:
Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany

Richter, A.
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h-index: 0
机构:
Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany

Richter, A.
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h-index: 0
机构:
Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany

Overkamp, T.
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h-index: 0
机构:
Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany

Essmann, F.
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h-index: 0
机构:
Univ Tubingen, Interfac Inst Biochem, Tubingen, Germany Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany

Hemmati, P. G.
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机构:
Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany

Preissner, R.
论文数: 0 引用数: 0
h-index: 0
机构:
Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany

Belka, C.
论文数: 0 引用数: 0
h-index: 0
机构:
Univ Munich, Dept Radiotherapy & Radiat Oncol, Munich, Germany Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany

Daniel, P. T.
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h-index: 0
机构:
Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany
Max Delbruck Ctr Mol Med, Dept Clin & Mol Oncol, Berlin, Germany Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany
机构:
[1] Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-10099 Berlin, Germany
[2] Univ Tubingen, Interfac Inst Biochem, Tubingen, Germany
[3] Univ Munich, Dept Radiotherapy & Radiat Oncol, Munich, Germany
[4] Max Delbruck Ctr Mol Med, Dept Clin & Mol Oncol, Berlin, Germany
来源:
CELL DEATH & DISEASE
|
2013年
/
4卷
关键词:
TRAIL;
XIAP;
SMAC;
Bax;
Bak;
apoptosis;
MEDIATED APOPTOSIS;
CANCER-CELLS;
BAX;
EXPRESSION;
INHIBITOR;
PROTEINS;
MCL-1;
ACTIVATION;
CASPASE-8;
CLEAVAGE;
D O I:
10.1038/cddis.2013.67
中图分类号:
Q2 [细胞生物学];
学科分类号:
071009 ;
090102 ;
摘要:
TRAIL is a promising anticancer agent, capable of inducing apoptosis in a wide range of treatment-resistant tumor cells. In 'type II' cells, the death signal triggered by TRAIL requires amplification via the mitochondrial apoptosis pathway. Consequently, deregulation of the intrinsic apoptosis-signaling pathway, for example, by loss of Bax and Bak, confers TRAIL-resistance and limits its application. Here, we show that despite resistance of Bax/Bak double-deficient cells, TRAIL-treatment resulted in caspase-8 activation and complete processing of the caspase-3 proenzymes. However, active caspase-3 was degraded by the proteasome and not detectable unless the XIAP/proteasome pathway was inhibited. Direct or indirect inhibition of XIAP by RNAi, Mithramycin A or by the SMAC mimetic LBW-242 as well as inhibition of the proteasome by Bortezomib overcomes TRAIL-resistance of Bax/Bak double-deficient tumor cells. Moreover, activation and stabilization of caspase-3 becomes independent of mitochondrial death signaling, demonstrating that inhibition of the XIAP/proteasome pathway overcomes resistance by converting 'type II' to 'type I' cells. Our results further demonstrate that the E3 ubiquitin ligase XIAP is a gatekeeper critical for the 'type II' phenotype. Pharmacological manipulation of XIAP therefore is a promising strategy to sensitize cells for TRAIL and to overcome TRAIL-resistance in case of central defects in the intrinsic apoptosis-signaling pathway.
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收藏
页码:e643 / e643
页数:10
相关论文
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h-index: 0
机构:
SUNY Upstate Med Univ, Dept Pharmacol, Syracuse, NY 13210 USA SUNY Upstate Med Univ, Dept Pharmacol, Syracuse, NY 13210 USA

Huang, Y
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SUNY Upstate Med Univ, Dept Pharmacol, Syracuse, NY 13210 USA SUNY Upstate Med Univ, Dept Pharmacol, Syracuse, NY 13210 USA

Sheikh, MS
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SUNY Upstate Med Univ, Dept Pharmacol, Syracuse, NY 13210 USA SUNY Upstate Med Univ, Dept Pharmacol, Syracuse, NY 13210 USA