title: Catalase inhibits ionizing radiation-induced apoptosis in hematopoietic stem and progenitor cells.
abstract: Hematologic toxicity is a major cause of mortality in radiation emergency scenarios and a primary side effect concern in patients undergoing chemo-radiotherapy. Therefore, there is a critical need for the development of novel and more effective approaches to manage this side effect. Catalase is a potent antioxidant enzyme that coverts hydrogen peroxide into hydrogen and water. In this study, we evaluated the efficacy of catalase as a protectant against ionizing radiation (IR)-induced toxicity in hematopoietic stem and progenitor cells (HSPCs). The results revealed that catalase treatment markedly inhibits IR-induced apoptosis in murine hematopoietic stem cells and hematopoietic progenitor cells. Subsequent colony-forming cell and cobble-stone area-forming cell assays showed that catalase-treated HSPCs can not only survive irradiation-induced apoptosis but also have higher clonogenic capacity, compared with vehicle-treated cells. Moreover, transplantation of catalase-treated irradiated HSPCs results in high levels of multi-lineage and long-term engraftments, whereas vehicle-treated irradiated HSPCs exhibit very limited hematopoiesis reconstituting capacity. Mechanistically, catalase treatment attenuates IR-induced DNA double-strand breaks and inhibits reactive oxygen species. Unexpectedly, we found that the radioprotective effect of catalase is associated with activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway and pharmacological inhibition of STAT3 abolishes the protective activity of catalase, suggesting that catalase may protect HSPCs against IR-induced toxicity via promoting STAT3 activation. Collectively, these results demonstrate a previously unrecognized mechanism by which catalase inhibits IR-induced DNA damage and apoptosis in HSPCs.
authors.affiliation: 1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.|2Department of Hematology, Tianjin First Center Hospital, Tianjin, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Xiao
authors.affiliation: 1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.|3Department of Histology and Embryology, University of South China, Hengyang City, Hunan Province, People's Republic of China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Luo
authors.affiliation: 4Department of Radiation Oncology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Vanek
authors.affiliation: 1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.|5Research Services, Ralph H. Johnson VAMC, Charleston, South Carolina.|6Cancer Genes and Molecular Regulation Program of the Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: LaRue
authors.affiliation: 1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Schulte
authors.affiliation: 1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.|6Cancer Genes and Molecular Regulation Program of the Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Wang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D002374:Catalase / Q000494:pharmacology*; D002478:Cells, Cultured; D004249:DNA Damage; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011839:Radiation, Ionizing; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D002374:Catalase