Caspase-3 Promotes Genetic Instability and Carcinogenesis

Abstract

Summary 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 Endo G activity significantly reduced radiation-induced DNA damage and oncogenic transformation, identifying Endo G 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.

A fate worse than death: apoptosis as an oncogenic process

“…Recent data show that cells which initiate apoptosis but do not die -we term this failed-apoptosis-sustain potentially oncogenic damage such as genomic instability and gene amplification (Figure 3) [71][72][73] . The failure to commit suicide is puzzling given what we know about apoptosis.…”

“…Finally, the level of caspase activity that is required to kill a cell does not appear to be very high 76 . These points notwithstanding, various studies have found that cells can engage caspase activity and survive, sustaining damage in the process [71][72][73]70 Intense interest has surrounded the potential of TRAIL ligands as anticancer therapies because many tumour-types are selectively sensitive to TRAIL-mediated apoptosis 77 . One of the first studies that demonstrated engagement of caspases activity in the absence of cell death focused on TRAIL-induced apoptosis 78 .…”

“…Moreover, transgenic expression of pro-apoptotic BAX has been found to promote lymphomagenesischaracterised by genomic instability-in a manner that is suppressed by co-expressing anti-apoptotic BCL-2 84 . Besides CAD, the mitochondrial nuclease Endo G has also been found to promote radiation-induced DNA damage and transformation 73 . Implicating a direct role for caspase-3, deletion of caspase-3 inhibited transformation following DNA-damage and reduced tumourigenesis in a chemically induced model of skin-cancer 73 .…”

“…Besides CAD, the mitochondrial nuclease Endo G has also been found to promote radiation-induced DNA damage and transformation 73 . Implicating a direct role for caspase-3, deletion of caspase-3 inhibited transformation following DNA-damage and reduced tumourigenesis in a chemically induced model of skin-cancer 73 .…”

A matter of regeneration and repair: caspases as the key molecules

“…Thus, surviving doses of TRAIL provokes mutagenesis through caspase-8 activation. In a more recent study, Liu et al (2015) showed that sublethal activation of caspase-3, after exposure to ionizing radiation, leads to genomic instability, oncogenic transformation, and increased tumorigenic nature in MCF10A mammalian cells, and the downstream effector of caspase-3 is EndoG in this damage. Absence of caspase-3 reduced these alterations.…”