Cell cycle progression and transmitotic apoptosis resistance promote escape from extrinsic apoptosis

Abstract

Extrinsic apoptosis relies on TNF-family receptor activation by immune cells or receptor-activating biologics. Here, we monitored cell cycle progression at minutes resolution to relate apoptosis kinetics and cell-to-cell heterogeneities in death decisions to cell cycle phases. Interestingly, we found that cells in S phase delay TRAIL receptor-induced death in favour for mitosis, thereby passing on an apoptosis-primed state to their offspring. This translates into two distinct fates, apoptosis execution post mitosis or cell survival from inefficient apoptosis. Transmitotic resistance is linked to Mcl-1 upregulation and increased accumulation at mitochondria from mid S phase onwards, which allows cells to pass through mitosis with activated caspase-8, and with cells escaping apoptosis after mitosis sustaining sublethal DNA damage. Antagonizing Mcl-1 suppresses cell cycle-dependent delays in apoptosis, prevents apoptosis-resistant progression through mitosis and averts unwanted survival from apoptosis induction. Cell cycle progression therefore modulates signal transduction during extrinsic apoptosis, with Mcl-1 governing decision making between death, proliferation and survival. Cell cycle progression thus is a crucial process from which cell-to-cell heterogeneities in fates and treatment outcomes emerge in isogenic cell populations during extrinsic apoptosis.

Cell survival following direct executioner-caspase activation

“…Anastasis is defined as survival from a transient stimulus that activates executioner-caspase and would be lethal if sustained. It has been observed in multiple cell types in vitro ( 21 – 28 ) and in vivo—in mouse neurons ( 29 ) and in multiple Drosophila tissues ( 30 – 32 ). Molecular mechanisms supporting cell survival include proteins such as Snail, Akt1, and dCIZ1 ( 26 , 31 ).…”

Bcl-xL activity influences outcome of the mitotic arrest

“…Large body of evidence suggests that cell death during mitotic arrest and after mitotic slippage proceeds via mitochondria dependent apoptotic pathway through p53 activation ( Gascoigne and Taylor, 2008 ; Orth et al, 2012 ; Jun and Kim, 2016 ; Pedley and Gilmore, 2016 ; Yasuhira et al, 2016 ; Ruan et al, 2019 ) or through extrinsic pathway ( Chang et al, 2009 ; Pollak et al, 2021 ). Execution of both apoptotic pathways converges to MOMP (mitochondrial outer membrane permeabilization) and further proceeds through activation of executive caspases ( Vorobjev and Barteneva, 2015 ; Vorobjev and Barteneva, 2016 ; Kalkavan and Green, 2018 ).…”

Effectiveness of an “online + in‐person” hybrid model for an undergraduate molecular biology lab during COVID‐19

“…As the most common process of programmed cell death, apoptosis can be triggered by multiple chemical and biological factors. This concept is highly relevant to a wide of range of disciplines, including biology, physiology, toxicology, and medicine 22–24 . Overall, the experimental session of this curriculum aims to cover the principles of apoptosis as well as commonly used techniques, such as immunocytochemistry (ICC), q‐PCR analysis, and western blot 25 .…”

“…This concept is highly relevant to a wide of range of disciplines, including biology, physiology, toxicology, and medicine. [22][23][24] Overall, the experimental session of this curriculum aims to cover the principles of apoptosis as well as commonly used techniques, such as immunocytochemistry (ICC), q-PCR analysis, and western blot. 25 We evaluated the students' mastery of the experimental content and laboratory skills under this teaching model through various assessments.…”