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. [1 ]
Richter, A. [1 ]
Richter, A. [1 ]
Overkamp, T. [1 ]
Essmann, F. [2 ]
Hemmati, P. G. [1 ]
Preissner, R. [1 ]
Belka, C. [3 ]
Daniel, P. T. [1 ,4 ]
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.
引用
收藏
页码:e643 / e643
页数:10
相关论文
共 41 条
[1]   Bortezomib Sensitizes Human Renal Cell Carcinomas to TRAIL Apoptosis through Increased Activation of Caspase-8 in the Death-Inducing Signaling Complex [J].
Brooks, Alan D. ;
Jacobsen, Kristen M. ;
Li, Wenqing ;
Shanker, Anil ;
Sayers, Thomas J. .
MOLECULAR CANCER RESEARCH, 2010, 8 (05) :729-738
[2]   Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM) [J].
Chauhan, Dharminder ;
Neri, Paola ;
Velankar, Mugdha ;
Podar, Klaus ;
Hideshima, Teru ;
Fulciniti, Mariateresa ;
Tassone, Pierfrancesco ;
Raje, Noopur ;
Mitsiades, Constantine ;
Mitsiades, Nicholas ;
Richardson, Paul ;
Zawel, Leigh ;
Tran, Mary ;
Munshi, Nikhil ;
Anderson, Kenneth C. .
BLOOD, 2007, 109 (03) :1220-1227
[3]   Bortezomib Overcomes Tumor Necrosis Factor-related Apoptosis-inducing Ligand Resistance in Hepatocellular Carcinoma Cells in Part through the Inhibition of the Phosphatidylinositol 3-Kinase/Akt Pathway [J].
Chen, Kuen-Feng ;
Yeh, Pei-Yen ;
Hsu, Chiun ;
Hsu, Chih-Hung ;
Lu, Yen-Shen ;
Hsieh, Hsing-Pang ;
Chen, Pei-Jer ;
Cheng, Ann-Lii .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (17) :11121-11133
[4]   IAP family proteins - suppressors of apoptosis [J].
Deveraux, QL ;
Reed, TC .
GENES & DEVELOPMENT, 1999, 13 (03) :239-252
[5]   Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases [J].
Deveraux, QL ;
Leo, E ;
Stennicke, HR ;
Welsh, K ;
Salvesen, GS ;
Reed, JC .
EMBO JOURNAL, 1999, 18 (19) :5242-5251
[6]   Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition [J].
Du, CY ;
Fang, M ;
Li, YC ;
Li, L ;
Wang, XD .
CELL, 2000, 102 (01) :33-42
[7]   Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis [J].
Gillissen, Bernhard ;
Essmann, Frank ;
Hemmati, Philipp G. ;
Richter, Antje ;
Richter, Anja ;
Oeztop, Ilker ;
Chinnadurai, Govindaswamy ;
Doerken, Bernd ;
Daniel, Peter T. .
JOURNAL OF CELL BIOLOGY, 2007, 179 (04) :701-715
[8]   Endogenous Bak inhibitors Mcl-1 and Bcl-xL: differential impact on TRAIL resistance in Bax-deficient carcinoma [J].
Gillissen, Bernhard ;
Wendt, Jana ;
Richter, Antje ;
Richter, Anja ;
Mueer, Annika ;
Overkamp, Tim ;
Gebhardt, Nina ;
Preissner, Robert ;
Belka, Claus ;
Doerken, Bernd ;
Daniel, Peter T. .
JOURNAL OF CELL BIOLOGY, 2010, 188 (06) :851-862
[9]   New insights into apoptosis signaling by Apo2L/TRAIL [J].
Gonzalvez, F. ;
Ashkenazi, A. .
ONCOGENE, 2010, 29 (34) :4752-4765
[10]   Proteasome inhibitor MG132 upregulates death receptor 5 and cooperates with Apo2L/TRAIL to induce apoptosis in Bax-proficient and -deficient cells [J].
He, Q ;
Huang, Y ;
Sheikh, MS .
ONCOGENE, 2004, 23 (14) :2554-2558