Casmir Turnquist1, Jessica A Beck1, Izumi Horikawa1, Ifeyinwa E Obiorah2, Natalia Von Muhlinen1, Borivoj Vojtesek3, David P Lane4, Christopher Grunseich5, Joeffrey J Chahine2, Heather M Ames6,7, Dee Dee Smart8, Brent T Harris2,9, Curtis C Harris1. 1. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 2. Department of Pathology, Georgetown University Medical Center, Washington, DC, USA. 3. Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic. 4. p53 Laboratory, Biomedical Sciences Institutes (A*STAR), Singapore. 5. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. 6. Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland, USA. 7. Department of Pathology, University of Maryland, Baltimore, Maryland, USA. 8. Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 9. Department of Neurology, Georgetown University Medical Center, Washington, DC, USA.
Abstract
BACKGROUND: Cellular senescence and the senescence-associated secretory phenotype (SASP) may contribute to the development of radiation therapy-associated side effects in the lung and blood vessels by promoting chronic inflammation. In the brain, inflammation contributes to the development of neurologic disease, including Alzheimer's disease. In this study, we investigated the roles of cellular senescence and Δ133p53, an inhibitory isoform of p53, in radiation-induced brain injury. METHODS: Senescent cell types in irradiated human brain were identified with immunohistochemical labeling of senescence-associated proteins p16INK4A and heterochromatin protein Hp1γ in 13 patient cases, including 7 irradiated samples. To investigate the impact of radiation on astrocytes specifically, primary human astrocytes were irradiated and examined for expression of Δ133p53 and induction of SASP. Lentiviral expression of ∆133p53 was performed to investigate its role in regulating radiation-induced cellular senescence and astrocyte-mediated neuroinflammation. RESULTS: Astrocytes expressing p16INK4A and Hp1γ were identified in all irradiated tissues, were increased in number in irradiated compared with untreated cancer patient tissues, and had higher labeling intensity in irradiated tissues compared with age-matched controls. Human astrocytes irradiated in vitro also experience induction of cellular senescence, have diminished Δ133p53, and adopt a neurotoxic phenotype as demonstrated by increased senescence-associated beta-galactosidase activity, p16INK4A, and interleukin (IL)-6. In human astrocytes, Δ133p53 inhibits radiation-induced senescence, promotes DNA double-strand break repair, and prevents astrocyte-mediated neuroinflammation and neurotoxicity. CONCLUSIONS: Restoring expression of the endogenous p53 isoform, ∆133p53, protects astrocytes from radiation-induced senescence, promotes DNA repair, and inhibits astrocyte-mediated neuroinflammation. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2019.
BACKGROUND: Cellular senescence and the senescence-associated secretory phenotype (SASP) may contribute to the development of radiation therapy-associated side effects in the lung and blood vessels by promoting chronic inflammation. In the brain, inflammation contributes to the development of neurologic disease, including Alzheimer's disease. In this study, we investigated the roles of cellular senescence and Δ133p53, an inhibitory isoform of p53, in radiation-induced brain injury. METHODS: Senescent cell types in irradiated human brain were identified with immunohistochemical labeling of senescence-associated proteins p16INK4A and heterochromatin protein Hp1γ in 13 patient cases, including 7 irradiated samples. To investigate the impact of radiation on astrocytes specifically, primary human astrocytes were irradiated and examined for expression of Δ133p53 and induction of SASP. Lentiviral expression of ∆133p53 was performed to investigate its role in regulating radiation-induced cellular senescence and astrocyte-mediated neuroinflammation. RESULTS: Astrocytes expressing p16INK4A and Hp1γ were identified in all irradiated tissues, were increased in number in irradiated compared with untreated cancerpatient tissues, and had higher labeling intensity in irradiated tissues compared with age-matched controls. Human astrocytes irradiated in vitro also experience induction of cellular senescence, have diminished Δ133p53, and adopt a neurotoxic phenotype as demonstrated by increased senescence-associated beta-galactosidase activity, p16INK4A, and interleukin (IL)-6. In human astrocytes, Δ133p53 inhibits radiation-induced senescence, promotes DNA double-strand break repair, and prevents astrocyte-mediated neuroinflammation and neurotoxicity. CONCLUSIONS: Restoring expression of the endogenous p53 isoform, ∆133p53, protects astrocytes from radiation-induced senescence, promotes DNA repair, and inhibits astrocyte-mediated neuroinflammation. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2019.
Authors: Shinichiro Mizumatsu; Michelle L Monje; Duncan R Morhardt; Radoslaw Rola; Theo D Palmer; John R Fike Journal: Cancer Res Date: 2003-07-15 Impact factor: 12.701
Authors: J H Silber; J Radcliffe; V Peckham; G Perilongo; P Kishnani; M Fridman; J W Goldwein; A T Meadows Journal: J Clin Oncol Date: 1992-09 Impact factor: 44.544
Authors: Jane J Sohn; Aaron J Schetter; Harris G Yfantis; Lisa A Ridnour; Izumi Horikawa; Mohammed A Khan; Ana I Robles; S Perwez Hussain; Akiteru Goto; Elise D Bowman; Lorne J Hofseth; Jirina Bartkova; Jiri Bartek; Gerald N Wogan; David A Wink; Curtis C Harris Journal: PLoS One Date: 2012-09-06 Impact factor: 3.240
Authors: Dana Greene-Schloesser; Mike E Robbins; Ann M Peiffer; Edward G Shaw; Kenneth T Wheeler; Michael D Chan Journal: Front Oncol Date: 2012-07-19 Impact factor: 6.244
Authors: Alistaire D Ruggiero; Matthew A Davis; Ashley T Davis; Darla DeStephanis; Abigail G Williams; Ravichandra Vemuri; Katherine M Fanning; Chrissy Sherrill; J Mark Cline; David L Caudell; Kylie Kavanagh Journal: Geroscience Date: 2022-09-22 Impact factor: 7.581
Authors: Andriy Yabluchanskiy; Stefano Tarantini; Priya Balasubramanian; Tamas Kiss; Tamas Csipo; Gábor A Fülöp; Agnes Lipecz; Chetan Ahire; Jordan DelFavero; Adam Nyul-Toth; William E Sonntag; Michal L Schwartzman; Judith Campisi; Anna Csiszar; Zoltan Ungvari Journal: Geroscience Date: 2020-01-20 Impact factor: 7.713
Authors: Marjan Boerma; Catherine M Davis; Isabel L Jackson; Dörthe Schaue; Jacqueline P Williams Journal: Int J Radiat Biol Date: 2021-07-01 Impact factor: 2.694
Authors: Ibrahim Y Abdelgawad; Karim T Sadak; Diana W Lone; Mohamed S Dabour; Laura J Niedernhofer; Beshay N Zordoky Journal: Pharmacol Ther Date: 2020-12-01 Impact factor: 12.310