The NOXA–MCL1–BIM axis defines lifespan on extended mitotic arrest

Abstract

Cell death on extended mitotic arrest is considered arguably most critical for the efficacy of microtubule-targeting agents (MTAs) in anticancer therapy. While the molecular machinery controlling mitotic arrest on MTA treatment, the spindle assembly checkpoint (SAC), appears well defined, the molecular components executing cell death, as well as factors connecting both networks remain poorly understood. Here we conduct a mini screen exploring systematically the contribution of individual BCL2 family proteins at single cell resolution to death on extended mitotic arrest, and demonstrate that the mitotic phosphorylation of BCL2 and BCLX represent a priming event for apoptosis that is ultimately triggered by NOXA-dependent MCL1 degradation, enabling BIM-dependent cell death. Our findings provide a comprehensive model for the initiation of apoptosis in cells stalled in mitosis and provide a molecular basis for the increased efficacy of combinatorial treatment of cancer cells using MTAs and BH3 mimetics.

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

“…15 MCL-1 is involved in regulation of both death in mitosis and death after mitotic slippage. [50][51][52] Mitotic degradation of MCL-1 can increase the probability of death in mitosis when MYC or NOXA is downregulated. 50,52 It can also hasten slippage during mitotic arrest caused by inhibitors of mitosis and increase the probability of apoptosis after slippage.…”

“…[50][51][52] Mitotic degradation of MCL-1 can increase the probability of death in mitosis when MYC or NOXA is downregulated. 50,52 It can also hasten slippage during mitotic arrest caused by inhibitors of mitosis and increase the probability of apoptosis after slippage. 51 While it is unclear if apoptosis induced by the belinostat-vincristine combination occurs during mitosis or after mitotic slippage, the concomitant downregulation of MCL-1 and upregulation of BIM could contribute to either.…”

Boosting the apoptotic response of high‐grade serous ovarian cancers with CCNE1 amplification to paclitaxel in vitro by targeting APC/C and the pro‐survival protein MCL‐1

“…Interestingly, several studies linked the activation of the apoptotic machinery with the duration of mitosis. Hereby, the induced myeloid leukemia cell differentiation protein (MCL‐1) was identified as the protein linking the time of mitosis to the induction of apoptosis . The pro‐survival function of MCL‐1 lies in its ability to bind and sequester BAX and BAK preventing them from forming pores in the mitochondrial membrane thereby triggering apoptosis .…”

Proteasome inhibition enhances the efficacy of volasertib-induced mitotic arrest in AML in vitro and prolongs survival in vivo

“…A reduction in Mcl-1 expression levels by targeted degradation is a trigger of cell death during mitotic block [31]. Therefore, we asked whether low Mcl-1 expression levels in AML cells make these cells a priori more vulnerable to antimitotic treatment when the application of an antimitotic agent and a proteasome inhibitor are combined.…”