title: Protracted upregulation of leptin and IGF1 is associated with activation of PI3K/Akt and JAK2 pathway in mouse intestine after ionizing radiation exposure.
abstract: Ionizing radiation is a known risk factor for gastrointestinal (GI) pathologies including cancer. Hormones and related signaling crosstalk, which could contribute to radiation-induced persistent pathophysiologic changes in the small intestine and colon, remain to be explored. The current study assessed perturbation of GI homeostasis-related hormones and signaling pathways at the systemic as well as at the tissue level in small intestine and colon. Mice (6-8 week old C57BL/6J) were exposed to 2 Gy γ radiation, serum and tissue samples were collected, and insulin like growth factor 1 (IGF-1) and leptin signaling were assessed two or twelve months after radiation exposure. Serum levels of IGF-1, IGF binding protein 3 (IGFBP3), leptin, and adiponectin were altered at these times after irradiation. Radiation was associated with increased IGF1 receptor (IGF1R) and obesity (leptin) receptor (Ob-R), decreased adiponectin receptor 1 (Adipo-R1) and 2 (Adipo-R2), and increased Ki-67 levels in small intestine and colon at both time points. Immunoblot analysis further showed increased IGF1R and Ob-R, and decreased Adipo-R2. Additionally, upregulation of PI3K/Akt and JAK2 signaling, which are downstream of IGF1 and leptin, was also observed in irradiated samples at both time points. These results when considered along with increased cell proliferation in the small intestine and colon demonstrate for the first time that ionizing radiation can persistently increase IGF1 and leptin and activate downstream proliferative pathways, which may contribute to GI functional alterations and carcinogenesis.
authors: 1. Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
authors: Shubhankar
authors: S
authors: Suman
authors: 2. Department of Pathology, Georgetown University Medical Center, Washington DC, USA.
authors: Bhaskar V S
authors: BV
authors: Kallakury
authors: 1. Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA. ; 3. Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia.
authors: Albert J
authors: AJ
authors: Fornace
authors: 1. Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
authors: Kamal
authors: K
authors: Datta
mesh_terms: D052242:Adiponectin / Q000097:blood; D000818:Animals; D049109:Cell Proliferation / Q000528:radiation effects; D005260:Female; D005720:Gamma Rays; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000528:radiation effects*; D053614:Janus Kinase 2 / Q000378:metabolism*; D020738:Leptin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D052242:Adiponectin; D018972:Insulin-Like Growth Factor Binding Protein 3; D020738:Leptin; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2
keywords: colorectal cancer; insulin like growth factor 1; intestinal homeostasis; ionizing radiation; leptin