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Mol Cell. 2015 Apr 16;58(2):284-96. doi: 10.1016/j.molcel.2015.03.003. Epub 2015 Apr 9.

Caspase-3 promotes genetic instability and carcinogenesis.

Author information

1
Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.
2
Department of General Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
3
Cancer Center, First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
4
Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
5
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.

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.

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PMID:
25866249
PMCID:
PMC4408780
DOI:
10.1016/j.molcel.2015.03.003
[Indexed for MEDLINE]
Free PMC Article

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