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

Oncotarget
TaeWoo KwonBuHyun Youn

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.

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Citations

Sep 22, 2019·Cells·Wanyeon KimBuHyun Youn
Oct 30, 2019·Nature Materials·Bo YangMichael P Sheetz
Nov 26, 2016·Experimental & Molecular Medicine·Wanyeon KimBuHyun Youn
Aug 12, 2017·American Journal of Physiology. Lung Cellular and Molecular Physiology·Beomseok SonBuHyun Youn
Jun 30, 2019·International Journal of Molecular Sciences·Nami KimTae Ho Lee
Jul 5, 2018·Cancer Metastasis Reviews·Wanyeon KimBuHyun Youn
Jun 11, 2021·Cellular Signalling·Changchun CaoLianshu Ding

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Methods Mentioned

BETA
immunoprecipitation
transfection
xenograft
PCR

Software Mentioned

DANGER
densitometric
Image J

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis