Proteasome inhibitors block DNA repair and radiosensitize non-small cell lung cancer

PLoS One. 2013 Sep 5;8(9):e73710. doi: 10.1371/journal.pone.0073710. eCollection 2013.

Abstract

Despite optimal radiation therapy (RT), chemotherapy and/or surgery, a majority of patients with locally advanced non-small cell lung cancer (NSCLC) fail treatment. To identify novel gene targets for improved tumor control, we performed whole genome RNAi screens to identify knockdowns that most reproducibly increase NSCLC cytotoxicity. These screens identified several proteasome subunits among top hits, including the topmost hit PSMA1, a component of the core 20 S proteasome. Radiation and proteasome inhibition showed synergistic effects. Proteasome inhibition resulted in an 80-90% decrease in homologous recombination (HR), a 50% decrease in expression of NF-κB-inducible HR genes BRCA1 and FANCD2, and a reduction of BRCA1, FANCD2 and RAD51 ionizing radiation-induced foci. IκBα RNAi knockdown rescued NSCLC radioresistance. Irradiation of mice with NCI-H460 xenografts after inducible PSMA1 shRNA knockdown markedly increased murine survival compared to either treatment alone. Proteasome inhibition is a promising strategy for NSCLC radiosensitization via inhibition of NF-κB-mediated expression of Fanconi Anemia/HR DNA repair genes.

Publication types

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

MeSH terms

  • Animals
  • BRCA1 Protein / genetics
  • Boronic Acids / pharmacology
  • Bortezomib
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / therapy*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cell Survival / radiation effects
  • Combined Modality Therapy
  • DNA Repair / genetics*
  • Fanconi Anemia Complementation Group D2 Protein / genetics
  • Female
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy*
  • Mice
  • Mice, Nude
  • NF-kappa B / genetics
  • Proteasome Endopeptidase Complex / genetics*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors / pharmacology
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Pyrazines / pharmacology
  • RNA Interference*
  • Rad51 Recombinase / genetics
  • Radiation, Ionizing
  • Radiation-Sensitizing Agents / pharmacology
  • Radiotherapy / methods
  • Reverse Transcriptase Polymerase Chain Reaction
  • Xenograft Model Antitumor Assays

Substances

  • BRCA1 Protein
  • Boronic Acids
  • Fanconi Anemia Complementation Group D2 Protein
  • NF-kappa B
  • Proteasome Inhibitors
  • Protein Subunits
  • Pyrazines
  • Radiation-Sensitizing Agents
  • Bortezomib
  • Rad51 Recombinase
  • PSMA1 protein, human
  • Proteasome Endopeptidase Complex