DANGER is involved in high glucose-induced radioresistance through inhibiting DAPK-mediated anoikis in non-small cell lung cancer

// TaeWoo Kwon 1, * , HyeSook Youn 2, 3, * , Beomseok Son 1, * , Daehoon Kim 1 , Ki Moon Seong 4 , Sungkyun Park 5 , Wanyeon Kim 2, 3 , BuHyun Youn 1, 2, 3 1 Department of Integrated Biological Science, Pusan National University, Busan, 609-735, Republic of Korea 2 Department of Biological Sciences, Pusan National University, Busan, 609-735, Republic of Korea 3 Nuclear Science Research Institute, Pusan National University, Busan, 609-735, Republic of Korea 4 National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Sciences, Seoul, 139-706, Republic of Korea 5 Department of Physics, Pusan National University, Busan, 609-735, Republic of Korea * These authors have contributed equally to this work Correspondence to: BuHyun Youn, e-mail: bhyoun72@pusan.ac.kr Wanyeon Kim, e-mail: wykim8282@gmail.com Keywords: radioresistance, high glucose, DANGER, DAPK, anoikis Received: September 13, 2015 Accepted: January 05, 2016 Published: January 12, 2016 ABSTRACT 18 F-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.