BH3 Mimetic ABT-737 Potentiates TRAIL-Mediated Apoptotic Signaling by Unsequestering Bim and Bak in Human Pancreatic Cancer Cells
- 15 April 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (8), 2944-2951
- https://doi.org/10.1158/0008-5472.can-07-2508
Abstract
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has been shown to induce mitochondrial apoptotic signaling that can be negatively regulated by prosurvival Bcl-2 proteins. ABT-737 is a small-molecule BH3 mimetic that binds to and antagonizes Bcl-2/Bcl-xL but not Mcl-1. We show that ABT-737 can synergistically enhance TRAIL-mediated cytotoxicity in human pancreatic cancer cell lines. ABT-737 was shown to enhance TRAIL-induced apoptosis as shown by DNA fragmentation, activation of caspase-8 and Bid, and cleavage of caspase-3 and poly(ADP-ribose) polymerase. A Bax conformational change induced by TRAIL was enhanced by ABT-737. ABT-737 disrupted the interaction of Bak with Bcl-xL in both cell lines. Furthermore, ABT-737 untethered the proapoptotic BH3-only protein Bim from its sequestration by Bcl-xL or Bcl-2. Bim small hairpin RNA (shRNA) was shown to attenuate caspase-3 cleavage and to reduce the cytotoxic effects of TRAIL plus ABT-737 compared with shRNA control cells. Finally, Mcl-1 shRNA potentiated caspase-3 cleavage by ABT-737 and enhanced its cytotoxic effects. Taken together, ABT-737 augments TRAIL-induced cell killing by unsequestering Bim and Bak and enhancing a Bax conformational change induced by TRAIL. These findings suggest a novel strategy to enhance cross-talk between the extrinsic and intrinsic apoptotic pathways to improve therapeutic efficacy against pancreatic cancer. [Cancer Res 2008;68(8):2944–51]Other Versions
This publication has 35 references indexed in Scilit:
- Reduction of TRAIL-Induced Mcl-1 and cIAP2 by c-Myc or Sorafenib Sensitizes Resistant Human Cancer Cells to TRAIL-Induced DeathCancer Cell, 2007
- Structural insights into the degradation of Mcl-1 induced by BH3 domainsProceedings of the National Academy of Sciences of the United States of America, 2007
- The Bcl-2 apoptotic switch in cancer development and therapyOncogene, 2007
- The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of BakBlood, 2007
- Mcl-1 Down-regulation Potentiates ABT-737 Lethality by Cooperatively Inducing Bak Activation and Bax TranslocationCancer Research, 2007
- Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737JCI Insight, 2007
- ‘Seed’ analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737Oncogene, 2006
- Identification of Inhibitors of TRAIL-induced Death (ITIDs) in the TRAIL-sensitive Colon Carcinoma Cell Line SW480 Using a Genetic ApproachOnline Journal of Public Health Informatics, 2001
- Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines.2001
- Bcl-XL protects pancreatic adenocarcinoma cells against CD95- and TRAIL-receptor-mediated apoptosisOncogene, 2000