title: Caspase-3 promotes genetic instability and carcinogenesis.
abstract: Apoptosis is typically considered an anti-oncogenic process since caspase activation can promote the elimination of genetically unstable or damaged cells. We report that a central effector of apoptosis, caspase-3, facilitates rather than suppresses chemical- and radiation-induced genetic instability and carcinogenesis. We found that a significant fraction of mammalian cells treated with ionizing radiation can survive despite caspase-3 activation. Moreover, this sublethal activation of caspase-3 promoted persistent DNA damage and oncogenic transformation. In addition, chemically induced skin carcinogenesis was significantly reduced in mice genetically deficient in caspase-3. Furthermore, attenuation of EndoG activity significantly reduced radiation-induced DNA damage and oncogenic transformation, identifying EndoG as a downstream effector of caspase-3 in this pathway. Our findings suggest that rather than acting as a broad inhibitor of carcinogenesis, caspase-3 activation may contribute to genome instability and play a pivotal role in tumor formation following damage.
authors: Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Xinjian
authors: X
authors: Liu
authors: Department of General Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors: Yujun
authors: Y
authors: He
authors: Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Fang
authors: F
authors: Li
authors: Cancer Center, First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
authors: Qian
authors: Q
authors: Huang
authors: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors: Takamitsu A
authors: TA
authors: Kato
authors: Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Russell P
authors: RP
authors: Hall
authors: Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: chuan.li@duke.edu.
authors: Chuan-Yuan
authors: CY
authors: Li
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000528:radiation effects; D001940:Breast / Q000166:cytology / Q000528:radiation effects; D053148:Caspase 3 / Q000378:metabolism*; D002478:Cells, Cultured; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D016678:Genome / Q000528:radiation effects*; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate
chemical_list: D015127:9,10-Dimethyl-1,2-benzanthracene; D004706:Endodeoxyribonucleases; C052391:endonuclease G; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D013755:Tetradecanoylphorbol Acetate