Format

Send to

Choose Destination
Cell Rep. 2016 Dec 20;17(12):3347-3358. doi: 10.1016/j.celrep.2016.11.064.

Tight Sequestration of BH3 Proteins by BCL-xL at Subcellular Membranes Contributes to Apoptotic Resistance.

Author information

1
CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France.
2
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
3
Cancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
4
CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France; ICO René Gauducheau, 44805 Saint Herblain, France. Electronic address: fabien.gautier@univ-nantes.fr.
5
CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France; ICO René Gauducheau, 44805 Saint Herblain, France. Electronic address: philippe.juin@univ-nantes.fr.

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.

KEYWORDS:

BCL-xL; BH3 mimetic resistance; membrane localization

PMID:
28009301
DOI:
10.1016/j.celrep.2016.11.064
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center