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Radioresistance of Serpinb3a-/- Mice and Derived Hematopoietic and Marrow Stromal Cell Lines.

Authors
  • Thermozier, Stephanie1
  • Zhang, Xichen1
  • Hou, Wen1
  • Fisher, Renee1
  • Epperly, Michael W1
  • Liu, Bing2
  • Bahar, Ivet2
  • Wang, Hong3
  • Greenberger, Joel S1
  • 1 Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania 15213.
  • 2 Department of Computational Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
  • 3 Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
Type
Published Article
Journal
Radiation Research
Publisher
BioOne (Radiation Research Society)
Publication Date
Sep 01, 2019
Volume
192
Issue
3
Pages
267–281
Identifiers
DOI: 10.1667/RR15379.1
PMID: 31295086
Source
Medline
Language
English
License
Unknown

Abstract

Serpins are a group of serine-proteases involved in multiple signal transduction pathways in mammalian cells. In particular, Serpinb3a is involved in the lysosomal necrosis cell death pathway with components that overlap with radiation-induced apoptosis. We investigated the radiation response of Serpinb3a-/- mice compared to Serpinb3a+/+ mice on the Balb/c background. Serpinb3a-/- mice showed significant radioresistance to a dose of 8.0 Gy total-body irradiation, compared to Serpinb3a+/+ Balb/c mice. Long-term bone marrow cultures from Serpinb3a-/- mice showed increased longevity. In clonogenic survival assays, fresh bone marrow hematopoietic progenitors, as well as clonal interleukin-3 (IL-3)-dependent hematopoietic progenitor and bone marrow stromal cell lines from Serpinb3a-/- mice were radioresistant. Serpinb3a-/- mouse bone marrow-derived stromal cell lines had increased baseline and postirradiation antioxidant capacity. Serpinb3a-/- bone marrow stromal cells showed increased radiation-induced RNA transcripts for MnSOD and p21, and decreased levels of p53 and TGF-b. Both irradiated Serpinb3a-/- mouse bone marrow stromal cell lines and plasma removed from total-body irradiated mice had decreased levels of expression of stress response and inflammation-associated proteins. Abrogation of Serpinb3a may be a potential new target for mitigation of radiation effects.

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