title: The Growing Complexity of Cancer Cell Response to DNA-Damaging Agents: Caspase 3 Mediates Cell Death or Survival?
abstract: It is widely stated that wild-type p53 either mediates the activation of cell cycle checkpoints to facilitate DNA repair and promote cell survival, or orchestrates apoptotic cell death following exposure to cancer therapeutic agents. This reigning paradigm has been challenged by numerous discoveries with different human cell types, including solid tumor-derived cell lines. Thus, activation of the p53 signaling pathway by ionizing radiation and other DNA-damaging agents hinders apoptosis and triggers growth arrest (e.g., through premature senescence) in some genetic backgrounds; such growth arrested cells remain viable, secrete growth-promoting factors, and give rise to progeny with stem cell-like properties. In addition, caspase 3, which is best known for its role in the execution phase of apoptosis, has been recently reported to facilitate (rather than suppress) DNA damage-induced genomic instability and carcinogenesis. This observation is consistent with an earlier report demonstrating that caspase 3 mediates secretion of the pro-survival factor prostaglandin E₂, which in turn promotes enrichment of tumor repopulating cells. In this article, we review these and related discoveries and point out novel cancer therapeutic strategies. One of our objectives is to demonstrate the growing complexity of the DNA damage response beyond the conventional "repair and survive, or die" hypothesis.
authors.affiliation: Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada. razmik.mirzayans@ahs.ca.
authors.forename: Razmik
authors.initials: R
authors.lastname: Mirzayans
authors.affiliation: Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada. bonnie.andrais@ahs.ca.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Andrais
authors.affiliation: Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada. pkumar@ualberta.ca.
authors.forename: Piyush
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada. david.murray5@ahs.ca.
authors.forename: David
authors.initials: D
authors.lastname: Murray
mesh_terms: D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D002470:Cell Survival; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D009153:Mutagens / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D009153:Mutagens; D053148:Caspase 3; D015232:Dinoprostone
keywords: Caspase 3; DNA damage response; DNA double-strand breaks; apoptosis; ionizing radiation; multinucleation; p21WAF1 (CDKN1A); premature senescence; prostaglandin E2; γH2AX foci