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

• Published in: Biochemical and biophysical research communications 2014-07, Vol.449 (4), p.471-476
• Main Authors: Yun, Hong Shik, Baek, Jeong-Hwa, Yim, Ji-Hye, Lee, Su-Jae, Lee, Chang-Woo, Song, Jie-Young, Um, Hong-Duck, Park, Jong Kuk, Park, In-Chul, Hwang, Sang-Gu
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ANTINEOPLASTIC DRUGS; ANTIOXIDANTS; APOPTOSIS; Apoptosis - drug effects; BIOLOGICAL MARKERS; Cell Line, Tumor; Cytoskeletal Proteins; Gene Knockdown Techniques; GROWTH FACTORS; H1299 cells; HEPATOMAS; HRP-3; Humans; INHIBITION; Intracellular Signaling Peptides and Proteins; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; LUNGS; Myc/Noxa signaling; NF-kappa B - metabolism; NF-κB; Nuclear Proteins - genetics; OXYGEN; PHENOTYPE; RADIOSENSITIVITY; Reactive Oxygen Species - metabolism; ROS; TUMOR CELLS; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2014.05.039

•HRP-3 is a radiation- and anticancer drug-responsive protein in H1299 cells.•Depletion of HRP-3 induces apoptosis of radio- and chemoresistant H1299 cells.•Depletion of HRP-3 promotes ROS generation via inhibition of the Nrf2/HO-1 pathway.•ROS generation enhances NF-κB activity, which acts as an upstream signal in the c-Myc/Noxa apoptotic pathway. 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.