Inhibiting autophagy flux and DNA repair of tumor cells to boost radiotherapy of orthotopic glioblastoma

Qi Xu; Hao Zhang; Hanghang Liu; Yaobao Han; Weibao Qiu; Zhen Li

doi:10.1016/j.biomaterials.2021.121287

Inhibiting autophagy flux and DNA repair of tumor cells to boost radiotherapy of orthotopic glioblastoma

Biomaterials. 2022 Jan:280:121287. doi: 10.1016/j.biomaterials.2021.121287. Epub 2021 Nov 29.

Authors

Qi Xu¹, Hao Zhang², Hanghang Liu¹, Yaobao Han¹, Weibao Qiu³, Zhen Li⁴

Affiliations

¹ Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, P.R. China.
² Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, P.R. China; College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, P.R. China. Electronic address: zhanghaoqf@suda.edu.cn.
³ Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P.R. China.
⁴ Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, P.R. China. Electronic address: zhenli@suda.edu.cn.

PMID: 34864449
DOI: 10.1016/j.biomaterials.2021.121287

Abstract

Radio-resistance of glioblastoma (GBM) remains a leading cause of radiotherapy failure because of the protective autophagy induced by X-Ray irradiation and tumor cells' strong capability of repairing damaged DNA. It is of great importance to overcome the radio-resistance for improving the efficacy of radiotherapy. Herein, we report the novel mechanism of core-shell copper selenide coated gold nanoparticles (Au@Cu_2-xSe NPs) inhibiting the protective autophagy and DNA repair of tumor cells to drastically boost the radiotherapy efficacy of glioblastoma. We reveal that the core-shell Au@Cu_2-xSe NPs can inhibit the autophagy flux by effectively alkalizing lysosomes. They can increase the SQSTM1/p62 protein levels of tumor cells without influencing their mRNA. We also reveal that Au@Cu_2-xSe NPs can increase the ubiquitination of DNA repair protein Rad51, and promote the degradation of Rad51 by proteasomes to prevent the DNA repair. The simultaneous inhibition of protective autophagy and DNA repair significantly suppress the growth of orthotopic GBM by using radiotherapy and our novel Au@Cu_2-xSe NPs. Our work provides a new insight and paradigm to significantly improve the efficacy of radiotherapy by rationally designing theranostic nano-agents to simultaneously inhibit protective autophagy and DNA repair of tumor cells.

Keywords: Autophagy; DNA repair; Glioblastoma; Radio-resistance; Radiotherapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autophagy
Cell Line, Tumor
DNA Repair
Glioblastoma* / genetics
Glioblastoma* / metabolism
Glioblastoma* / radiotherapy
Gold / pharmacology
Humans
Metal Nanoparticles*

Substances

Gold