Caspase-3 Promotes Genetic Instability and Carcinogenesis

• DOI: 10.1016/j.molcel.2015.03.003
• Publication Date: 2015-04-11T11:22:41Z
• Authors: Xinjian Liu; Yujun He; Fang Li; Qian Huang; Takamitsu A. Kato; Russell P. Hall; Chuan-Yuan Li
• Keywords: Endodeoxyribonucleases; Genome; Skin Neoplasms; Caspase 3; 9,10-Dimethyl-1,2-benzanthracene; Bone Marrow Cells; Epithelial Cells; Neoplasms, Experimental; Genomic Instability; Mice; Animals; Humans; Tetradecanoylphorbol Acetate; Female; Breast; Cells, Cultured

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.