title: TGF-β and Hypoxia/Reoxygenation Promote Radioresistance of A549 Lung Cancer Cells through Activation of Nrf2 and EGFR.
abstract: Although many studies have examined the roles of hypoxia and transforming growth factor- (TGF-) β separately in the tumor microenvironment, the effects of simultaneous treatment with hypoxia/reoxygenation and TGF-β on tumor malignancy are unclear. Here, we investigated the effects of redox signaling and oncogenes on cell proliferation and radioresistance in A549 human lung cancer cells in the presence of TGF-β under hypoxia/reoxygenation conditions. Combined treatment with TGF-β and hypoxia activated epidermal growth factor receptor (EGFR) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a redox-sensitive transcription factor. Interestingly, Nrf2 knockdown suppressed the effects of combined treatment on EGFR phosphorylation. In addition, blockade of EGFR signaling also suppressed induction of Nrf2 following combined treatment with hypoxia and TGF-β, indicating that the combined treatment induced positive crosstalk between Nrf2 and EGFR. TGF-β and hypoxia/reoxygenation increased the accumulation of reactive oxygen species (ROS), while treatment with N-acetyl-l-cysteine abolished the activation of Nrf2 and EGFR. Treatment with TGF-β under hypoxic conditions increased the proliferation of A549 cells compared with that after vehicle treatment. Moreover, cells treated with the combined treatment exhibited resistance to ionizing radiation (IR), and knockdown of Nrf2 increased IR-induced cell death under these conditions. Thus, taken together, our findings suggested that TGF-β and hypoxia/reoxygenation promoted tumor progression and radioresistance of A549 cells through ROS-mediated activation of Nrf2 and EGFR.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors.forename: Sae-lo-oom
authors.initials: SL
authors.lastname: Lee
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors.forename: Hwani
authors.initials: H
authors.lastname: Ryu
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors.forename: A-rang
authors.initials: AR
authors.lastname: Son
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors.forename: Bitna
authors.initials: B
authors.lastname: Seo
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors.forename: Jooyoung
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors.forename: Seung-Youn
authors.initials: SY
authors.lastname: Jung
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors.forename: Jie-Young
authors.initials: JY
authors.lastname: Song
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Ahn
mesh_terms: D000072283:A549 Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D008024:Ligands; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen