title: Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response.
abstract: Apoptosis serves as a protective mechanism by eliminating damaged cells through programmed cell death. After apoptotic cells pass critical checkpoints, including mitochondrial fragmentation, executioner caspase activation, and DNA damage, it is assumed that cell death inevitably follows. However, this assumption has not been tested directly. Here we report an unexpected reversal of late-stage apoptosis in primary liver and heart cells, macrophages, NIH 3T3 fibroblasts, cervical cancer HeLa cells, and brain cells. After exposure to an inducer of apoptosis, cells exhibited multiple morphological and biochemical hallmarks of late-stage apoptosis, including mitochondrial fragmentation, caspase-3 activation, and DNA damage. Surprisingly, the vast majority of dying cells arrested the apoptotic process and recovered when the inducer was washed away. Of importance, some cells acquired permanent genetic changes and underwent oncogenic transformation at a higher frequency than controls. Global gene expression analysis identified a molecular signature of the reversal process. We propose that reversal of apoptosis is an unanticipated mechanism to rescue cells from crisis and propose to name this mechanism "anastasis" (Greek for "rising to life"). Whereas carcinogenesis represents a harmful side effect, potential benefits of anastasis could include preservation of cells that are difficult to replace and stress-induced genetic diversity.
authors.affiliation: Center for Cell Dynamics, Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. holamtang@jhmi.edu
authors.forename: Ho Lam
authors.initials: HL
authors.lastname: Tang
authors.forename: Ho Man
authors.initials: HM
authors.lastname: Tang
authors.forename: Keng Hou
authors.initials: KH
authors.lastname: Mak
authors.forename: Shaomin
authors.initials: S
authors.lastname: Hu
authors.forename: Shan Shan
authors.initials: SS
authors.lastname: Wang
authors.forename: Kit Man
authors.initials: KM
authors.lastname: Wong
authors.forename: Chung Sing Timothy
authors.initials: CS
authors.lastname: Wong
authors.forename: Hoi Yan
authors.initials: HY
authors.lastname: Wu
authors.forename: Hiu Tung
authors.initials: HT
authors.lastname: Law
authors.forename: Kan
authors.initials: K
authors.lastname: Liu
authors.forename: C Conover
authors.initials: CC
authors.lastname: Talbot
authors.forename: Wan Keung
authors.initials: WK
authors.lastname: Lau
authors.forename: Denise J
authors.initials: DJ
authors.lastname: Montell
authors.forename: Ming Chiu
authors.initials: MC
authors.lastname: Fung
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D004249:DNA Damage; D047630:Depsipeptides / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D020869:Gene Expression Profiling; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics
chemical_list: D000891:Anti-Infective Agents, Local; D000970:Antineoplastic Agents; D047630:Depsipeptides; C057531:jasplakinolide; D000431:Ethanol