ABT-737 promotes tBid mitochondrial accumulation to enhance TRAIL-induced apoptosis in glioblastoma cells
- To search for novel strategies to enhance the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis pathways in glioblastoma, we used the B-cell lymphoma 2/Bcl2-like 2-inhibitor ABT-737. Here we report that ABT-737 and TRAIL cooperate to induce apoptosis in several glioblastoma cell lines in a highly synergistic manner (combination index <0.1). Interestingly, the concerted action of ABT-737 and TRAIL to trigger the accumulation of truncated Bid (tBid) at mitochondrial membranes is identified as a key underlying mechanism. ABT-737 and TRAIL cooperate to cleave BH3-interacting domain death agonist (Bid) into its active fragment tBid, leading to increased accumulation of tBid at mitochondrial membranes. Coinciding with tBid accumulation, the activation of Bcl2-associated X protein (Bax), loss of mitochondrial membrane potential, release of cytochrome-c and second mitochondria-derived activator of caspase (Smac) into the cytosol and caspase activation are strongly increased in cotreated cells. Of note, knockdown of Bid significantly decreases ABT-737- and TRAIL-mediated Bax activation and apoptosis. Also, caspase-3 silencing reduces ABT-737- and TRAIL-induced Bid cleavage and apoptosis, indicating that a caspase-3-driven, mitochondrial feedback loop contributes to Bid processing. Importantly, ABT-737 profoundly enhances TRAIL-triggered apoptosis in primary cultured glioblastoma cells derived from tumor material, underlining the clinical relevance. Also, ABT-737 acts in concert with TRAIL to suppress tumor growth in an in vivo glioblastoma model. In conclusion, the rational combination of ABT-737 and TRAIL cooperates to trigger tBid mitochondrial accumulation and apoptosis. This approach presents a promising strategy for targeting the apoptosis pathways in glioblastoma, which warrants further investigation.
Author: | Silvia Cristofanon, Simone FuldaORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-288951 |
DOI: | https://doi.org/10.1038/cddis.2012.163 |
ISSN: | 2041-4889 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/23190604 |
Parent Title (English): | Cell death & disease |
Publisher: | Nature Publishing Group |
Place of publication: | London [u.a.] |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2012/11/29 |
Date of first Publication: | 2012/11/29 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2013/02/14 |
Tag: | ABT-737; TRAIL; apoptosis |
Volume: | 3 |
Issue: | e432 |
Page Number: | 11 |
Note: | This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/. |
HeBIS-PPN: | 331605678 |
Institutes: | Medizin / Medizin |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - Namensnennung-Nicht kommerziell 3.0 |