Knockdown of hepatoma-derived growth factor-related protein-3 induces apoptosis of H1299 cells via ROS-dependent and p53-independent NF-κB activation

Biochem Biophys Res Commun. 2014 Jul 11;449(4):471-6. doi: 10.1016/j.bbrc.2014.05.039. Epub 2014 May 22.

Abstract

We previously identified hepatoma-derived growth factor-related protein-3 (HRP-3) as a radioresistant biomarker in p53 wild-type A549 cells and found that p53-dependent induction of the PUMA pathway was a critical event in regulating the radioresistant phenotype. Here, we found that HRP-3 knockdown regulates the radioresistance of p53-null H1299 cells through a distinctly different molecular mechanism. HRP-3 depletion was sufficient to cause apoptosis of H1299 cells by generating substantial levels of reactive oxygen species (ROS) through inhibition of the Nrf2/HO-1 antioxidant pathway. Subsequent, ROS-dependent and p53-independent NF-κB activation stimulated expression of c-Myc and Noxa proteins, thereby inducing the apoptotic machinery. Our results thus extend the range of targets for the development of new drugs to treat both p53 wild-type or p53-null radioresistant lung cancer cells.

Keywords: H1299 cells; HRP-3; Myc/Noxa signaling; NF-κB; ROS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cytoskeletal Proteins
  • Gene Knockdown Techniques
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / radiotherapy
  • NF-kappa B / metabolism*
  • Nuclear Proteins / genetics*
  • Reactive Oxygen Species / metabolism*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Cytoskeletal Proteins
  • HDGFL3 protein, human
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Nuclear Proteins
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53