Mutagenic Consequences of Sublethal Cell Death Signaling

Abstract

Many human cancers exhibit defects in key DNA damage response elements that can render tumors insensitive to the cell death-promoting properties of DNA-damaging therapies. Using agents that directly induce apoptosis by targeting apoptotic components, rather than relying on DNA damage to indirectly stimulate apoptosis of cancer cells, may overcome classical blocks exploited by cancer cells to evade apoptotic cell death. However, there is increasing evidence that cells surviving sublethal exposure to classical apoptotic signaling may recover with newly acquired genomic changes which may have oncogenic potential, and so could theoretically spur the development of subsequent cancers in cured patients. Encouragingly, cells surviving sublethal necroptotic signaling did not acquire mutations, suggesting that necroptosis-inducing anti-cancer drugs may be less likely to trigger therapy-related cancers. We are yet to develop effective direct inducers of other cell death pathways, and as such, data regarding the consequences of cells surviving sublethal stimulation of those pathways are still emerging. This review details the currently known mutagenic consequences of cells surviving different cell death signaling pathways, with implications for potential oncogenic transformation. Understanding the mechanisms of mutagenesis associated (or not) with various cell death pathways will guide us in the development of future therapeutics to minimize therapy-related side effects associated with DNA damage.

Spontaneous activity of the mitochondrial apoptosis pathway drives chromosomal defects, the appearance of micronuclei and cancer metastasis through the Caspase-Activated DNAse

“…The only known way to CAD-activation is by the caspasedependent cleavage of its inhibitor. This suggests that the CADdependent chromosomal misalignments and generation of micronuclei is the result of continuous, sub-lethal caspase-activity, which may arise as a consequence of low-level activity of the mitochondrial apoptosis apparatus (minority MOMP) as reported previously [7,9]. We tested this by targeting components of the mitochondrial apoptosis system.…”

“…It was however sufficient to activate the Caspaseactivated DNAse (CAD) by the caspase-dependent cleavage of its inhibitor ICAD [3,4]; CAD-activity in the absence of apoptosis had earlier been identified during prolonged mitotic arrest [5] and in live, differentiating myoblasts [6]. There is now substantial evidence that components of the apoptosis signaling pathway also function outside cell death; this includes caspases as well as DNAses, and both CAD and the mitochondrial DNAse EndoG have been implicated [7]. Proposed functions of these signals mostly concern cell differentiation [7,8].…”

“…There is now substantial evidence that components of the apoptosis signaling pathway also function outside cell death; this includes caspases as well as DNAses, and both CAD and the mitochondrial DNAse EndoG have been implicated [7]. Proposed functions of these signals mostly concern cell differentiation [7,8]. One study reported that spontaneous activity of the effector caspases-3, −6 and −7 in the breast cancer cell line MDA-MB-231 was required for spontaneously appearing DNA-damage through CAD and EndoG.…”

T cell-mediated additive cytotoxicity – death by multiple bullets

“…Different types of damage may concur and their efficacy relies on the cellspecific activity of their respective repair mechanisms, with analogies to apoptosis resistance observed in sublethal radio-or chemotherapy-induced cell stress. Incomplete or faulty repair of sublethal damage may carry the risk to increase cancer aggressiveness [68,69], highlighting the therapeutic importance of achieving lethal immunotargeting. As resistance to CTL attack occurs downstream to antigen recognition and lytic granule secretion, the efficacy of even highly specific engineered cytotoxic immune cell or activated immune cells following immune checkpoint modulation may be compromised by enhanced repair ability of tumor cells.…”

The Mutagenic Impact of Environmental Exposures in Human Cells and Cancer: Imprints Through Time

“…While aflatoxin B1 and aristocholic acid directly alkylate the DNA, several indirect mutagenic processes have been identified. External exposures can result in unsuccessful apoptosis ( Ichim et al, 2015 ; Hawkins and Miles, 2021 ) or altered expression of DNA replication and repair enzymes, elevating mutational loads ( Russo et al, 2019 ; Cipponi et al, 2020 ). As the mutagenicity of these processes has been determined using colony outgrowth assays or reporter gene assays, mutational signatures from these processes are lacking, and could be established in the future using WGS-based methods.…”