DANGER is involved in high glucose-induced radioresistance through inhibiting DAPK-mediated anoikis in non-small cell lung cancer
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TaeWoo Kwon1,*, HyeSook Youn2,3,*, Beomseok Son1,*, Daehoon Kim1, Ki Moon Seong4, Sungkyun Park5, Wanyeon Kim2,3, BuHyun Youn1,2,3
1Department of Integrated Biological Science, Pusan National University, Busan, 609-735, Republic of Korea
2Department of Biological Sciences, Pusan National University, Busan, 609-735, Republic of Korea
3Nuclear Science Research Institute, Pusan National University, Busan, 609-735, Republic of Korea
4National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Sciences, Seoul, 139-706, Republic of Korea
5Department of Physics, Pusan National University, Busan, 609-735, Republic of Korea
*These authors have contributed equally to this work
BuHyun Youn, e-mail: email@example.com
Wanyeon Kim, e-mail: firstname.lastname@example.org
Keywords: radioresistance, high glucose, DANGER, DAPK, anoikis
Received: September 13, 2015 Accepted: January 05, 2016 Published: January 12, 2016
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.
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