Abstract 3736: Space radiation-induced decline in gut autophagy and expansion of both mitotic and senescent population denotes an aging phenotype with enhanced cancer risk

Abstract

Abstract Exposure to space radiation is known to alter a myriad of cellular processes that could potentially affect astronauts’ health during and after long duration’s space missions. Due to high-LET (linear energy transfer) characteristics of energetic heavy ions (HZE) present in space, astronauts are predicted to be at higher risk for gastrointestinal cancer development. Proliferative epithelial cells in gastrointestinal (GI) tissue are highly radiosensitive and in our previous studies we have demonstrated a persistent stress phenotype in crypt cells after heavy ion space radiation exposure. However, uncertainty remains in our understanding of how heavy ions induce chronic stress and inflammation is linked to higher cancer risk. The purpose of the current study was to assess late effects of heavy ion (56-Fe) on the autophagy process that is required to recycle damaged cellular components and its role in HZE-induced gastrointestinal carcinogenesis. C57BL6/J mice were exposed to 1.6 Gy of 56-Fe radiation at NASA Space Radiation Laboratory (NSRL). Mice were euthanized 2-month after radiation and intestinal tissues were analyzed for oxidative stress and associated DNA damage, and alterations in antioxidant response and autophagy signaling. Further, cells underdoing mitosis, autophagy and stress-induced senescence were also scored and alterations in cell signaling pathways with established role in carcinogenesis were evaluated. Energetic heavy ions exposure resulted in a long-term increase in intracellular reactive oxygen species (ROS), accompanied with decreased expression of key antioxidant genes (Gpx, SOD and catalase). Increase in both mitochondrial and cytosolic ROS was evident as both loss of mitochondrial membrane potential (MMP) and increase in prooxidant Nox1 expression was found. Paradoxical increases in phospho-histone-3 positive (mitotic) and p16 positive (senescent) cells were found, however decreases in autophagy positive (LC3B) cells was noted in HZE-exposed mouse intestine. Upregulation of upstream mTOR-PI3K-AKT signaling and p62 were noticed in long-term suppression of autophagy (Atg12, LC3B and Beclin-1) after HZE-exposure. Here, we show that space radiation downregulated autophagy processes, which are an important cellular mechanism involved in suppression of carcinogenesis. When considered along with upregulation of proliferative pathways and increased oxidative stress, our data suggest increased risk of chronic GI diseases including cancer due to late persistence of damaged organelles in cells after energetic heavy ion radiation exposures. Collectively, this study demonstrates a unique phenomenon of heavy ion-induced suppression of autophagy concurrent with increases in both mitotic and senescent cells indicating a premature aging phenotype with enhanced cancer risk. Citation Format: Kamal Datta, Shubhankar Suman, Bo-Hyun Moon, Albert J. Fornace. Space radiation-induced decline in gut autophagy and expansion of both mitotic and senescent population denotes an aging phenotype with enhanced cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3736.