Abstract 852: Enhanced expression of secretory clusterin/apolipoprotein J (sCLU) in pulmonary alveolar stem cells after ionizing radiation exposure

Abstract

Ionizing radiation is commonly used in the treatment of broad range of malignancies. However radiation induces DNA damage and oxidative stress in malignant and normal cells and stimulates inflammation in irradiated tissues. These vents may lead to tumor cell death, but also to a range of side effects including self-limited acute toxicities, mild chronic symptoms, or severe organ dysfunction. Recently, we reported that accelerated senescence of type II pneumocytes, the alveolar stem cell, results in depletion of type II pneumocytes and precedes pulmonary fibrosis. Targeted isolated depletion of type II pneumocytes is known to result in fibrosis. To understand the underlying mechanisms between RIPF and senescence, we investigated the role of several molecules which were markedly changed in irradiated lungs with fibrogenic exposures. Secretory Clusterin/Apolipoprotein J (sCLU) is a heterodimeric disulfide-linked glycoprotein encoded by a single gene. sCLU expression is implicated in physiological processes including development, lipid transportation, differentiation, cellular senescence, and in many age-related diseases including neurodegeneration, vascular damage, diabetes and tumorigenesis. It was recently proposed that sCLU is a sensitive cellular biosensor of oxidative stress that functions to protect cells from the deleterious effects of free radicals and their derivatives. We investigated sCLU expression in primary murine pneumocytes after exposure to irradiation. Increased sCLU expression following irradiation was confirmed by immunocytochemical assays and quantitative real-time PCR in primary pneumocyte cultures. At 5 days after irradiation, sCLU expression colocalized with senescence-associated beta-galactosidase (SA-beta-gal) activity. To determine the temporal relationship between sCLU expression and SA-beta-gal activity, sCLU expression and SA-beta-galactosidase activity was measured in murine lung tissues at 2 and 4 weeks after radiation exposures. As observed in pneumocyte cultures, the expression of sCLU mRNA was significantly increased in murine lungs after fibrogenic irradiation, with staining colocalizing to cells staining positive for SA-beta-gal activity. IGF-1, known to induce sCLU expression, was positively correlated with the levels of sCLU in irradiated lungs. Inhibition of IGF-1 signaling reduced sCLU expression in primary pneumocytes exposed to fibrogenic irradiation. Collectively, these data suggest that sCLU may provide a marker or target of type II pneumocyte senescence after irradiation. Citation Format: Eunjoo Chung, Jason Horton, Ayla White, Bradly Scroggins, Kathryn Hudak, Deborah Citrin. Enhanced expression of secretory clusterin/apolipoprotein J (sCLU) in pulmonary alveolar stem cells after ionizing radiation exposure. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 852. doi:10.1158/1538-7445.AM2014-852