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Executioner caspases and CAD are essential for mutagenesis induced by TRAIL or vincristine

Mark A Miles1, Christine J Hawkins1

  • 1Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia.

Cell Death & Disease
|October 6, 2017
PubMed

Insights

Chemotherapy can cause mutations in surviving cells through DNA damage and apoptosis. This study reveals executioner caspases and CAD are key to these mutations, suggesting a link to therapy-related cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Chemotherapy induces DNA damage, activating cell death pathways and potentially causing mutations in surviving cells.
  • Therapy-related cancers can arise from mutations in non-cancerous cells due to sustained DNA damage.
  • Apoptotic pathways, like those triggered by TRAIL, can also lead to mutations.

Purpose of the Study:

  • To investigate the role of executioner caspases and CAD/DFF40 in chemotherapy-induced mutagenesis.
  • To determine if apoptotic signaling pathways contribute to mutations caused by conventional chemotherapy drugs.
  • To explore the non-apoptotic functions of caspases in mutagenesis.

Main Methods:

  • Investigated the role of caspase activation and CAD/DFF40 in TRAIL-induced mutations.
  • Assessed the dependence of chemotherapy-induced mutations on caspases and CAD.
  • Utilized specific chemotherapy agents including vincristine, doxorubicin, SN38, cisplatin, and temozolomide.

Main Results:

  • Executioner caspase activation of CAD/DFF40 is essential for TRAIL-induced mutations.
  • Vincristine-induced mutations were dependent on caspases and CAD.
  • Caspases contributed to mutations from doxorubicin and SN38 but were dispensable for cisplatin and temozolomide mutagenesis.

Conclusions:

  • Caspases play a non-apoptotic role in mutagenesis induced by death receptor agonists, microtubule poisons, and topoisomerase inhibitors.
  • Sublethal apoptotic signaling during anticancer therapy may have carcinogenic consequences.
  • Highlights a novel mechanism linking cancer therapy to secondary cancer risk.

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