title: DANGER is involved in high glucose-induced radioresistance through inhibiting DAPK-mediated anoikis in non-small cell lung cancer.
abstract: 18F-labeled fluorodeoxyglucose (FDG) uptake during FDG positron emission tomography seems to reflect increased radioresistance. However, the exact molecular mechanism underlying high glucose (HG)-induced radioresistance is unclear. In the current study, we showed that ionizing radiation-induced activation of the MEK-ERK-DAPK-p53 signaling axis is required for anoikis (anchorage-dependent apoptosis) of non-small cell lung cancer (NSCLC) cells in normal glucose media. Phosphorylation of DAPK at Ser734 by ERK was essential for p53 transcriptional activity and radiosensitization. In HG media, overexpressed DANGER directly bound to the death domain of DAPK, thus inhibiting the catalytic activity of DAPK. In addition, inhibition of the DAPK-p53 signaling axis by DANGER promoted anoikis-resistance and epithelial-mesenchymal transition (EMT), resulting in radioresistance of HG-treated NSCLC cells. Notably, knockdown of DANGER enhanced anoikis, EMT inhibition, and radiosensitization in a mouse xenograft model of lung cancer. Taken together, our findings offered evidence that overexpression of DANGER and the subsequent inhibitory effect on DAPK kinase activity are critical responses that account for HG-induced radioresistance of NSCLC.
authors.affiliation: Department of Integrated Biological Science, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: TaeWoo
authors.initials: T
authors.lastname: Kwon
authors.affiliation: Department of Biological Sciences, Pusan National University, Busan, 609-735, Republic of Korea.|Nuclear Science Research Institute, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: HyeSook
authors.initials: H
authors.lastname: Youn
authors.affiliation: Department of Integrated Biological Science, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Beomseok
authors.initials: B
authors.lastname: Son
authors.affiliation: Department of Integrated Biological Science, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Daehoon
authors.initials: D
authors.lastname: Kim
authors.affiliation: National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Sciences, Seoul, 139-706, Republic of Korea.
authors.forename: Ki Moon
authors.initials: KM
authors.lastname: Seong
authors.affiliation: Department of Physics, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Sungkyun
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, Pusan National University, Busan, 609-735, Republic of Korea.|Nuclear Science Research Institute, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Wanyeon
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Integrated Biological Science, Pusan National University, Busan, 609-735, Republic of Korea.|Department of Biological Sciences, Pusan National University, Busan, 609-735, Republic of Korea.|Nuclear Science Research Institute, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: BuHyun
authors.initials: B
authors.lastname: Youn
mesh_terms: D000818:Animals; D023102:Anoikis / Q000187:drug effects* / Q000528:radiation effects; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D049109:Cell Proliferation / Q000187:drug effects; D064550:Death-Associated Protein Kinases / Q000378:metabolism*; D005720:Gamma Rays / Q000009:adverse effects*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D011836:Radiation Tolerance / Q000187:drug effects*; D013549:Sweetening Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C516570:ITPRIP protein, human; D008565:Membrane Proteins; D013549:Sweetening Agents; D008156:Luciferases; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D005947:Glucose
keywords: DANGER; DAPK; anoikis; high glucose; radioresistance