1. Tight Sequestration of BH3 Proteins by BCL-xL at Subcellular Membranes Contributes to Apoptotic Resistance.
- Author
-
Pécot J, Maillet L, Le Pen J, Vuillier C, Trécesson SC, Fétiveau A, Sarosiek KA, Bock FJ, Braun F, Letai A, Tait SWG, Gautier F, and Juin PP
- Subjects
- Apoptosis Regulatory Proteins metabolism, Bcl-2-Like Protein 11 genetics, Cell Survival genetics, Cell-Free System, HCT116 Cells, Humans, Mitochondria metabolism, Neoplasms drug therapy, Peptide Fragments administration & dosage, Proto-Oncogene Proteins administration & dosage, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-bcl-2 genetics, bcl-X Protein metabolism, Apoptosis genetics, Apoptosis Regulatory Proteins genetics, Mitochondria genetics, Neoplasms genetics, bcl-X Protein genetics
- Abstract
Anti-apoptotic BCL-2 family members bind to BH3-only proteins and multidomain BAX/BAK to preserve mitochondrial integrity and maintain survival. Whereas inhibition of these interactions is the biological basis of BH3-mimetic anti-cancer therapy, the actual response of membrane-bound protein complexes to these compounds is currently ill-defined. Here, we find that treatment with BH3 mimetics targeting BCL-xL spares subsets of cells with the highest levels of this protein. In intact cells, sequestration of some pro-apoptotic activators (including PUMA and BIM) by full-length BCL-xL is much more resistant to derepression than previously described in cell-free systems. Alterations in the BCL-xL C-terminal anchor that impacts subcellular membrane-targeting and localization dynamics restore sensitivity. Thus, the membrane localization of BCL-xL enforces its control over cell survival and, importantly, limits the pro-apoptotic effects of BH3 mimetics by selectively influencing BCL-xL binding to key pro-apoptotic effectors., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF