Nicotinamide Adenine Dinucleotide Phosphate Oxidase Promotes Glioblastoma Radiation Resistance in a Phosphate and Tensin Homolog-Dependent Manner

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作   者：

Kirsten Ludwig;  Janel E. Le Belle;  Sree Deepthi Muthukrishnan;  Jantzen Sperry;  Michael Condro;  Erina Vlashi;  Frank Pajonk;  Harley I. Kornblum; 

作者机构：

Department of Radiation Oncology;  The Intellectual and Developmental Disabilities Research Center and the Department of Psychiatry;  David Geffen School of Medicine at UCLA; 

关键词：

p22phox;  hypoxia;  glioblastoma;  radiation;  NADPH oxidase;  PTEN;  glioma; 

期刊名称：

Antioxidants and redox signalling

i s s n：

1523-0864

年卷期：

2023 年 39 卷 13/15 期

页   码：

890-903

页   码：

摘   要：

Aims: The goal of this study was to determine whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-produced reactive oxygen species (ROS) enhance brain tumor growth of glioblastoma (GBM) under hypoxic conditions and during radiation treatment.Results: Exogenous ROS promoted brain tumor growth in gliomasphere cultures that expressed functional phosphate and tensin homolog (PTEN), but not in tumors that were PTEN deficient. Hypoxia induced the production of endogenous cytoplasmic ROS and tumor cell growth via activation of NOX. NOX activation resulted in oxidation of PTEN and downstream protein kinase B (Akt) activation. Radiation also promoted ROS production via NOX, which, in turn, resulted in cellular protection that could be abrogated by knockdown of the key NOX component, p22. Knockdown of p22 also inhibited tumor growth and enhanced the efficacy of radiation in PTEN-expressing GBM cells.Innovation: While other studies have implicated NOX function in GBM models, this study demonstrates NOX activation and function under physiological hypoxia and following radiation in GBM, two conditions that are seen in patients. NOX plays an important role in a PTEN-expressing GBM model system, but not in PTEN-nonfunctional systems, and provides a potential, patient-specific therapeutic opportunity.Conclusion: This study provides a strong basis for pursuing NOX inhibition in PTEN-expressing GBM cells as a possible adjunct to radiation therapy. Antioxid. Redox Signal. 39, 890–903.