MYC Is a Major Determinant of Mitotic Cell Fate

Abstract

SummaryTaxol and other antimitotic agents are frontline chemotherapy agents but the mechanisms responsible for patient benefit remain unclear. Following a genome-wide siRNA screen, we identified the oncogenic transcription factor Myc as a taxol sensitizer. Using time-lapse imaging to correlate mitotic behavior with cell fate, we show that Myc sensitizes cells to mitotic blockers and agents that accelerate mitotic progression. Myc achieves this by upregulating a cluster of redundant pro-apoptotic BH3-only proteins and suppressing pro-survival Bcl-xL. Gene expression analysis of breast cancers indicates that taxane responses correlate positively with Myc and negatively with Bcl-xL. Accordingly, pharmacological inhibition of Bcl-xL restores apoptosis in Myc-deficient cells. These results open up opportunities for biomarkers and combination therapies that could enhance traditional and second-generation antimitotic agents.

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

“…Upregulation of BIM was shown to increase the probability of cell death in mitosis in the presence of reduced MYC expression. 50 This is relevant to our study because we showed previously that belinostat strongly down-regulates MYC protein expression in DLBCL cell lines. 15 MCL-1 is involved in regulation of both death in mitosis and death after mitotic slippage.…”

“…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.…”

Mitosis and mitochondrial priming for apoptosis

“…Indeed, as Myc drives cell cycle progression (Daksis et al, 1994;Vlach et al, 1996;Pérez-Roger et al, 1997), it also alters the landscape of apoptotic gene expression to increase mitochondrial priming, up-regulating the BH3-only proteins Bid, Bim and NOXA and down-regulating anti-apoptotic Bcl-XL (Conacci-Sorrell et al, 2014). Conversely, inhibiting Myc reduces mitosis-associated priming (Topham et al, 2015). The outcome is to ensure that failure in correct chromosomal segregation activates mitochondrial apoptosis that is dependent upon Bax and Bak.…”

“…Thus, regulation of the pro-apoptotic Bcl-2 proteins must also be a key Brought to you by | MIT Libraries Authenticated Download Date | 5/11/18 11:06 AM part of regulating the DiM timer. To address this, siRNA screens for factors that favour DiM have been performed (Diaz-Martinez et al, 2014;Topham et al, 2015). Although the specific details vary, the results show that cells reposition their Bcl-2 expression profile prior to mitotic entry.…”