Caspase-8 promotes space radiation induced carcinogenesis
Abstract
The carcinogenic risk of space radiation is a major concern for manned space travel. In this study, we investigated a novel but counter-intuitive hypothesis that caspase-8, an apical caspase protease involved in death receptor-mediated apoptosis typically considered to be a tumor suppressor, promotes, rather than suppresses, space radiation-induced DNA damage and carcinogenesis. By use of a non-invasive caspase-8 reporter, we found that a significant fraction of mammalian cells exposed to low dose high energy (600MeV/µ) iron ions radiation (56Fe) can survive, despite caspase-8 activation. This sublethal activation of caspase-8 promoted persistent DNA damage and oncogenic transformation. Blocking caspase-8 activity could significantly decrease iron ions radiation-induced DNA damage and abolish oncogenic transformation in human cells and in mice model. Mechanistically, we identified that the survived caspase-8 activation cells showed limited mitochondrial outer membrane permeabilization, which caused sublethal caspase cascade activation and persistent endonuclease G migration from the mitochondria to the nucleus, where it causes DNA damage. Taken together, our findings indicate that low dose of iron ions radiation can induce persistent genetic instability, efficient oncogenic transformation by sublethal caspase- 8 activation. Since a wide array of environmental and endogenous stressors can trigger caspase activation, our findings suggest that caspase-8 activation may play a critical role in stress induced carcinogenesis in general.
- Publication:
-
43rd COSPAR Scientific Assembly. Held 28 January - 4 February
- Pub Date:
- January 2021
- Bibcode:
- 2021cosp...43E1830L