NAD+ depletion radiosensitizes 2-DG-treated glioma cells by abolishing metabolic adaptation.

Abstract

Two-deoxy-d-glucose (2-DG) mediated glucose restriction (GR) has been applied as a potential therapeutic strategy for tumor clinical treatments. However, increasing evidences have indicated that 2-DG alone is inefficient in killing tumor cells, and the effect of 2-DG on modifying tumor radio-responses also remains controversial. In this study, we found that 2-DG triggered metabolic adaption in U87 glioma cells by up-regulating nicotinamide phosphoribosyltransferase (NAMPT) and cellular NAD+ content, which abolished 2-DG-induced potential radiosensitizing effect in glioma cells. Strikingly, NAD+ depletion evoked notable oxidative stress by NADPH reduction and hence re-radiosensitized 2-DG-treated glioma cells. Furthermore, isocitrate dehydrogenase-1 (IDH1) mutant U87 glioma cells with deficiency in the rate-limiting enzyme of Preiss-Handler pathway nicotinate phosphoribosyltransferase (Naprt1) revealed notable 2-DG-induced oxidative stress and radiosensitization. Our findings implied that targeting NAD+ could radiosensitize gliomas with GR, and 2-DG administration could be benefit for tumor patients with IDH1 mutation.

• Authors: Xiaolin Shi, Wei Zhang, Cheng Gu, Huangge Ren, Chen Wang, Narui Yin, Zhongmin Wang, Jiahua Yu, Fenju Liu, Haowen Zhang
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 162 Pg. 514-522 (01 2021) ISSN: 1873-4596 [Electronic] United States
• PMID: 33197538 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• NAD
• NADP
• Isocitrate Dehydrogenase

Topics

• Cell Line, Tumor
• Glioma (drug therapy, genetics, radiotherapy)
• Humans
• Isocitrate Dehydrogenase (genetics)
• Mutation
• NAD
• NADP