title: Mouse embryonic stem cells undergo charontosis, a novel programmed cell death pathway dependent upon cathepsins, p53, and EndoG, in response to etoposide treatment.
abstract: Embryonic stem cells (ESCs) are hypersensitive to many DNA damaging agents and can rapidly undergo cell death or cell differentiation following exposure. Treatment of mouse ESCs (mESCs) with etoposide (ETO), a topoisomerase II poison, followed by a recovery period resulted in massive cell death with characteristics of a programmed cell death pathway (PCD). While cell death was both caspase- and necroptosis-independent, it was partially dependent on the activity of lysosomal proteases. A role for autophagy in the cell death process was eliminated, suggesting that ETO induces a novel PCD pathway in mESCs. Inhibition of p53 either as a transcription factor by pifithrin α or in its mitochondrial role by pifithrin μ significantly reduced ESC death levels. Finally, EndoG was newly identified as a protease participating in the DNA fragmentation observed during ETO-induced PCD. We coined the term charontosis after Charon, the ferryman of the dead in Greek mythology, to refer to the PCD signaling events induced by ETO in mESCs.
authors.affiliation: Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. tichyed@mail.uc.edu
authors.forename: Elisia D
authors.initials: ED
authors.lastname: Tichy
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Stephan
authors.forename: Andrew
authors.initials: A
authors.lastname: Osterburg
authors.forename: Greg
authors.initials: G
authors.lastname: Noel
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stambrook
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism*; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000378:metabolism; D005047:Etoposide / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D002403:Cathepsins; D020169:Caspases