TRAIL treatment provokes mutations in surviving cells

Abstract

Chemotherapy and radiotherapy commonly damage DNA and trigger p53-dependent apoptosis through intrinsic apoptotic pathways. Two unfortunate consequences of this mechanism are resistance due to blockade of p53 or intrinsic apoptosis pathways, and mutagenesis of non-malignant surviving cells which can impair cellular function or provoke second malignancies. Death ligand-based drugs, such as tumor necrosis factor-related apoptosis inducing ligand (TRAIL), stimulate extrinsic apoptotic signaling, and may overcome resistance to treatments that induce intrinsic apoptosis. As death receptor ligation does not damage DNA as a primary mechanism of pro-apoptotic action, we hypothesized that surviving cells would remain genetically unscathed, suggesting that death ligand-based therapies may avoid some of the adverse effects associated with traditional cancer treatments. Surprisingly, however, treatment with sub-lethal concentrations of TRAIL or FasL was mutagenic. Mutations arose in viable cells that contained active caspases, and overexpression of the caspase-8 inhibitor crmA or silencing of caspase-8 abolished TRAIL-mediated mutagenesis. Downregulation of the apoptotic nuclease caspase-activated DNAse (CAD)/DNA fragmentation factor 40 (DFF40) prevented the DNA damage associated with TRAIL treatment. Although death ligands do not need to damage DNA in order to induce apoptosis, surviving cells nevertheless incur DNA damage after treatment with these agents.

A fate worse than death: apoptosis as an oncogenic process

“…Supporting an oncogenic role for failed apoptosis following TRAIL-treatment, another study found that sub-lethal doses of TRAIL (and FAS ligand) led to caspase-dependent mutations and genomic instability in surviving cells 72 .…”

“…Recent data show that cells which initiate apoptosis but do not die -we term this failed-apoptosis-sustain potentially oncogenic damage such as genomic instability and gene amplification (Figure 3) [71][72][73] . The failure to commit suicide is puzzling given what we know about apoptosis.…”

“…Finally, the level of caspase activity that is required to kill a cell does not appear to be very high 76 . These points notwithstanding, various studies have found that cells can engage caspase activity and survive, sustaining damage in the process [71][72][73]70 Intense interest has surrounded the potential of TRAIL ligands as anticancer therapies because many tumour-types are selectively sensitive to TRAIL-mediated apoptosis 77 . One of the first studies that demonstrated engagement of caspases activity in the absence of cell death focused on TRAIL-induced apoptosis 78 .…”

“…Indeed, glioma cells and mouse fibroblasts surviving TRAIL treatment engage DNA damage in a caspase and CAD-dependent manner 72 (Figure 3). …”

A matter of regeneration and repair: caspases as the key molecules

“…In addition to the role in migration, another mission of caspase-8 has been unveiled. Exposing of sublethal doses of TRAIL, which is used to overcome resistance in intrinsic apoptotic pathways, caused DNA breaks in glioma and mouse embryonic fibroblasts (Lovric and Hawkins, 2010). It has been observed that these mutations occur through the activation of caspase-activated DNase (CAD), which is inhibited by active caspase-8 substrate, the inhibitor of CAD.…”