FoxM1-dependent RAD51 and BRCA2 signaling protects idiopathic pulmonary fibrosis fibroblasts from radiation-induced cell death

Cell Death Dis. 2018 May 22;9(6):584. doi: 10.1038/s41419-018-0652-4.

Abstract

Radiation therapy is critical for the control of many tumors and lung is an important dose-limiting organ that impacts radiation dose prescribed to avoid irreversible pulmonary fibrosis in cancer survivors. Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible lung disease caused by aberrantly activated lung (myo)fibroblasts. The presence of pro-fibrotic, apoptosis-resistant fibroblasts in IPF promotes progressive fibrosis and may have a role in other diseases, if these resistant cells are selected for as a consequence of treatment. However, the pathological response of IPF fibroblasts to radiation compared to non-IPF lung fibroblasts is not known. To address this, we examined fibroblast viability following radiation in lung fibroblasts from IPF and non-IPF patients and the underlying mechanism that protects IPF fibroblasts from radiation-induced death. IPF fibroblasts are significantly more resistant to apoptosis compared to non-IPF lung fibroblasts, suggesting that resistance to radiation-induced cell death is a predominant mechanism leading to lung fibrosis. Analysis of γH2AX induction demonstrated that radiation-induced DNA damage is reduced in IPF fibroblasts and correlates to the activation of the transcription factor forkhead box M1 (FoxM1) and subsequent upregulation of DNA repair proteins RAD51 and BRCA2. FoxM1 activation occurs secondary to FoxO3a suppression in IPF fibroblasts while restoration of FoxO3a function sensitizes IPF fibroblasts to radiation-induced cell death and downregulates FoxM1, RAD51, and BRCA2. Our findings support that increased FoxO3a/FoxM1-dependent DNA repair may be integral to the preservation of death-resistant fibrotic fibroblasts after radiation and that selective targeting of radioresistant fibroblasts may mitigate fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • BRCA2 Protein / metabolism*
  • Bleomycin
  • Cell Death
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Collagen / metabolism
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Breaks, Double-Stranded / radiation effects
  • DNA Fragmentation / drug effects
  • DNA Fragmentation / radiation effects
  • DNA Repair / drug effects
  • DNA Repair / radiation effects
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology*
  • Fibroblasts / radiation effects
  • Forkhead Box Protein M1 / metabolism*
  • Forkhead Box Protein O3 / metabolism
  • Histones / metabolism
  • Humans
  • Idiopathic Pulmonary Fibrosis / pathology*
  • Mutagens / toxicity
  • Rad51 Recombinase / metabolism*
  • Radiation Tolerance / drug effects
  • Radiation Tolerance / radiation effects
  • Radiation, Ionizing*
  • Signal Transduction*

Substances

  • BRCA2 Protein
  • BRCA2 protein, human
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Forkhead Box Protein O3
  • H2AX protein, human
  • Histones
  • Mutagens
  • Bleomycin
  • Collagen
  • RAD51 protein, human
  • Rad51 Recombinase