Venetoclax causes metabolic reprogramming independent of BCL-2 inhibition

Alba Roca-Portoles,Xu Luo,David Sumpton,Margaret Mullin,Gillian M Mackay,Leandro Lemgruber,Katelyn O’Neill,Giovanny Rodriguez-Blanco,Catherine Cloix,Stephen W G Tait

doi:10.1038/s41419-020-02867-2

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.

Highlights

IntroductionAnti-cancer therapies often kill cancer cells through the mitochondrial (intrinsic) pathway of apoptosis[1]
Anti-cancer therapies often kill cancer cells through the mitochondrial pathway of apoptosis[1]
Venetoclax treatment led to a decrease in CT26 basal oxygen consumption rate (OCR), indicating an inhibitory effect on mitochondrial oxidative phosphorylation (OXPHOS) (Fig. 1a)

Summary

Introduction

Anti-cancer therapies often kill cancer cells through the mitochondrial (intrinsic) pathway of apoptosis[1]. In this process, mitochondrial outer membrane permeabilisation (MOMP) is the key initiating event for cell death[2]. MOMP allows the release of mitochondrial proteins, including cytochrome c, that activate caspase proteases and apoptosis. Because of its central role in regulating life and death, MOMP is tightly regulated, primarily by BCL-2 protein family members. The BCL-2 family is comprised of pro-apoptotic BAX, BAK and BH3-only proteins and anti-apoptotic BCL-2 members[3].

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