title: Depletion of hepatoma-derived growth factor-related protein-3 induces apoptotic sensitization of radioresistant A549 cells via reactive oxygen species-dependent p53 activation.
abstract: 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.
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea; Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Hong Shik
authors.initials: HS
authors.lastname: Yun
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Hong
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jeong-Hwa
authors.initials: JH
authors.lastname: Baek
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Lee
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Yim
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins; D019008:Drug Resistance, Neoplasm; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D003598:Cytoskeletal Proteins; C498539:HDGFL3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
keywords: A549 cells; HRP-3; Nrf2/HO-1; ROS; p53/PUMA