Venetoclax causes metabolic reprogramming independent of BCL-2 inhibition

Roca Portoles, A., Blanco, G., Sumpton, D., Cloix, C., Mullin, M., Mackay, G. M., O'Neill, K., Lemgruber Soares, L. , Luo, X. and Tait, S. W.G. (2020) Venetoclax causes metabolic reprogramming independent of BCL-2 inhibition. Cell Death and Disease, 11, 616. (doi: 10.1038/s41419-020-02867-2) (PMID:32792521) (PMCID:PMC7426836)

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Abstract

BH3-mimetics are a new class of anti-cancer drugs that inhibit anti-apoptotic Bcl-2 proteins. In doing so, BH3-mimetics sensitise to cell death. Venetoclax is a potent, BCL-2 selective BH3-mimetic that is clinically approved for use in chronic lymphocytic leukaemia. Venetoclax has also been shown to inhibit mitochondrial metabolism, this is consistent with a proposed role for BCL-2 in metabolic regulation. We used venetoclax to understand BCL-2 metabolic function. Similar to others, we found that venetoclax inhibited mitochondrial respiration. In addition, we also found that venetoclax impairs TCA cycle activity leading to activation of reductive carboxylation. Importantly, the metabolic effects of venetoclax were independent of cell death because they were also observed in apoptosis-resistant BAX/BAK-deficient cells. However, unlike venetoclax treatment, inhibiting BCL-2 expression had no effect on mitochondrial respiration. Unexpectedly, we found that venetoclax also inhibited mitochondrial respiration and the TCA cycle in BCL-2 deficient cells and in cells lacking all anti-apoptotic BCL-2 family members. Investigating the basis of this off-target effect, we found that venetoclax-induced metabolic reprogramming was dependent upon the integrated stress response and ATF4 transcription factor. These data demonstrate that venetoclax affects cellular metabolism independent of BCL-2 inhibition. This off-target metabolic effect has potential to modulate venetoclax cytotoxicity.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sumpton, Mr David and Cloix, Dr Catherine and Roca, Alba and Mackay, Dr Gillian and Lemgruber Soares, Dr Leandro and Tait, Professor Stephen and Mullin, Mrs Margaret
Authors: Roca Portoles, A., Blanco, G., Sumpton, D., Cloix, C., Mullin, M., Mackay, G. M., O'Neill, K., Lemgruber Soares, L., Luo, X., and Tait, S. W.G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cell Death and Disease
Publisher:Nature Research
ISSN:2041-4889
ISSN (Online):2041-4889
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Cell Death and Disease 11:616
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172007Apoptosis as an oncogenic process: understanding and exploiting its dark-sideStephen TaitCancer Research UK (CRUK)C40872/A20145Institute of Cancer Sciences