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

• Published in: Biochemical and biophysical research communications 2013-09, Vol.439 (3), p.333-339
• Main Authors: Yun, Hong Shik, Hong, Eun-Hee, Lee, Su-Jae, Baek, Jeong-Hwa, Lee, Chang-Woo, Yim, Ji-Hye, Um, Hong-Duck, Hwang, Sang-Gu
• Format: Article
• Language: English
• Subjects: A549 cells; Anticarcinogenic Agents - pharmacology; ANTINEOPLASTIC DRUGS; ANTIOXIDANTS; APOPTOSIS; Apoptosis - drug effects; Apoptosis - radiation effects; BIOLOGICAL MARKERS; Cell Line, Tumor; CHEMOTHERAPY; Cytoskeletal Proteins; Drug Resistance, Neoplasm; GROWTH FACTORS; Heme Oxygenase-1 - metabolism; HEPATOMAS; HRP-3; Humans; INHIBITION; 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; LUNGS; NF-E2-Related Factor 2 - metabolism; Nrf2/HO-1; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; OXYGEN; p53/PUMA; PHENOTYPE; RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; RADIOLOGY AND NUCLEAR MEDICINE; RADIOSENSITIVITY; RADIOTHERAPY; Reactive Oxygen Species - metabolism; RNA Interference; ROS; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2013.08.086

•HRP-3 is a radiation- and anticancer drug-responsive protein in A549 cells.•Depletion of HRP-3 induces apoptosis of radio- and chemoresistant A549 cells.•Depletion of HRP-3 promotes ROS generation via inhibition of the Nrf2/HO-1 pathway.•Depletion of HRP-3 enhances ROS-dependent p53 activation and PUMA expression. 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.