Depletion of hepatoma-derived growth factor-related protein-3 induces apoptotic sensitization of radioresistant A549 cells via reactive oxygen species-dependent p53 activation

Biochem Biophys Res Commun. 2013 Sep 27;439(3):333-9. doi: 10.1016/j.bbrc.2013.08.086. Epub 2013 Sep 6.


Biomarkers based on functional signaling have the potential to provide greater insight into the pathogenesis of cancer and may offer additional targets for anticancer therapeutics. Here, we identified hepatoma-derived growth factor-related protein-3 (HRP-3) as a radioresistance-related gene and characterized the molecular mechanism by which its encoded protein regulates the radio- and chemoresistant phenotype of lung cancer-derived A549 cells. Knockdown of HRP-3 promoted apoptosis of A549 cells and potentiated the apoptosis-inducing action of radio- and chemotherapy. This increase in apoptosis was associated with a substantial generation of reactive oxygen species (ROS) that was attributable to inhibition of the Nrf2/HO-1 antioxidant pathway and resulted in enhanced ROS-dependent p53 activation and p53-dependent expression of PUMA (p53 upregulated modulator of apoptosis). Therefore, the HRP-3/Nrf2/HO-1/ROS/p53/PUMA cascade is an essential feature of the A549 cell phenotype and a potential radiotherapy target, extending the range of targets in multimodal therapies against lung cancer.

Keywords: A549 cells; HRP-3; Nrf2/HO-1; ROS; p53/PUMA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Cell Line, Tumor
  • Cytoskeletal Proteins
  • Drug Resistance, Neoplasm
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Lung / radiation effects
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Lung Neoplasms / radiotherapy*
  • NF-E2-Related Factor 2 / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • RNA Interference
  • Reactive Oxygen Species / metabolism*
  • Tumor Suppressor Protein p53 / metabolism*


  • Anticarcinogenic Agents
  • Cytoskeletal Proteins
  • HDGFL3 protein, human
  • Intracellular Signaling Peptides and Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Nuclear Proteins
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • HMOX1 protein, human
  • Heme Oxygenase-1