Caspase-3 promotes genetic instability and carcinogenesis.
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.
Liu, X; He, Y; Li, F; Huang, Q; Kato, TA; Hall, RP; Li, C-Y
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