Abstract
Chemotherapy drugs interfere with cellular processes to generate genotoxic lesions that activate cell death pathways. Sustained DNA damage induced by these drugs can provoke mutations in surviving non-cancerous cells, potentially increasing the risk of therapy-related cancers. Ligation of death receptors by ligands such as TRAIL, and subsequent activation of extrinsic apoptotic pathways, also provokes mutations. In this study, we show that executioner caspase activation of the apoptotic nuclease CAD/DFF40 is essential for TRAIL-induced mutations in surviving cells. As exposure to chemotherapy drugs also activates apoptotic caspases and presumably CAD, we hypothesized that these pathways may also contribute to the mutagenesis induced by conventional chemotherapy drugs, perhaps augmenting the mutations that arise from direct DNA damage provoked by these agents. Interestingly, vincristine-mediated mutations were caspase and CAD dependent. Executioner caspases accounted for some of the mutations caused by the topoisomerase poisons doxorubicin and SN38, but were dispensable for mutagenesis following treatment with cisplatin or temozolomide. These data highlight a non-apoptotic role of caspases in mutagenesis mediated by death receptor agonists, microtubule poisons and topoisomerase inhibitors, and provide further evidence for a potential carcinogenic consequence of sublethal apoptotic signaling stimulated by anticancer therapies.
Highlights
Conventional chemotherapy agents provoke DNA damage and/or perturb mitosis in order to trigger apoptotic pathways in tumor cells, to eliminate the patient’s cancer.[1]
To determine whether CAD is required for TRAIL-induced mutagenesis, we used CRISPR/Cas[9] gene-editing to generate TK6 derivatives lacking CAD expression (Figure 1a)
A ligation-mediated quantitative PCR method 'ApoqPCR'40 revealed that the level of apoptotic DNA was over fourfold higher in TRAIL-treated cells compared with untreated cells, hardly any fragmented DNA was detected in TRAIL-treated CAD KO lines (Figure 1b), CAD was the primary nuclease responsible for apoptotic DNA fragmentation in this context
Summary
Conventional chemotherapy agents provoke DNA damage and/or perturb mitosis in order to trigger apoptotic pathways in tumor cells, to eliminate the patient’s cancer.[1]. A number of these genotoxic lesions promote the activation of error-prone DNA repair mechanisms and surviving cells may acquire mutations.[8] mutagenic anticancer drugs may possess oncogenic potential and may promote the development of subsequent 'therapy-related' cancers in cured patients.[9]. Death receptor agonists, such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L), which directly activate extrinsic apoptosis, were mutagenic.[11] Ligation of TRAIL death receptors upon binding of the TRAIL ligand promotes the recruitment of FADD and caspases-8 and/or -10 to the cytoplasmic death inducing signaling complex (DISC), activating these initiator caspases.[12] Subsequent activation of executioner caspases-3 and -7 results either from direct cleavage by caspase-8 ('type I' cells) or via cleavage of the BH3-only protein Bid to stimulate Bax-/Bak-dependent MOMP ('type II' cells).[13] TRAIL and agonistic antibodies targeting. CAD exists in an inactive heterodimeric complex with its inhibitor and chaperone, ICAD/
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