Apoptosis and apoptotic caspases are generally considered tumor-suppressive since there are involved in the elimination of unwanted or damaged cells. However, the relationship between caspases and carcinogenesis has not been thoroughly examined. In this study, we sought to determine the role of caspase 3 in chemical- and radiation-induced genetic instability and carcinogenesis. By use of a non-invasive caspase 3 reporter, we found that that a significant fraction of mammalian cells treated with ionizing radiation could survive, despite caspase 3 activation. Moreover, this sublethal activation of caspase 3 promoted persistent DNA damage, chromosome aberrations and oncogenic transformation. In addition, chemically-induced skin carcinogenesis was significantly reduced in mice genetically deficient in caspase 3. We provided strong evidence that activated caspase 3 can indeed promote oncogenic transformation in human cells and in mice by inducing persistent genetic instability. Since a wide array of environmental and endogenous stressors can trigger caspase 3 activation, 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.

Citation Format: XINJIAN LIU, Fang Li, Chuan-yuan Li. A facilitative role for caspase 3 in promoting genetic instability and carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-087. doi:10.1158/1538-7445.AM2015-LB-087