Autophagy suppresses self-renewal ability and tumorigenicity of glioma-initiating cells and promotes Notch1 degradation

Zhennan Tao,Yingshuai Wang,Feng Yuan,Shengping Yu,Xuejun Yang,Yang Xie,Long Hai,Yihan Yang,Tao Li,Luqing Tong,Peidong Liu,Li Yi,Jiabo Li,Haolang Ming,Haiwen Ma,Chen Zhang

doi:10.1038/s41419-018-0957-3

Abstract

Autophagy is a vital process that involves degradation of long-lived proteins and dysfunctional organelles and contributes to cellular metabolism. Glioma-initiating cells (GICs) have the ability to self-renew, differentiate into heterogeneous types of tumor cells, and sustain tumorigenicity; thus, GICs lead to tumor recurrence. Accumulating evidence indicates that autophagy can induce stem cell differentiation and increase the lethality of temozolomide against GICs. However, the mechanism underlying the regulation of GIC self-renewal by autophagy remains uncharacterized. In the present study, autophagy induced by AZD8055 and rapamycin treatment suppressed GIC self-renewal in vitro. We found that autophagy inhibited Notch1 pathway activation. Moreover, autophagy activated Notch1 degradation, which is associated with maintenance of the self-renewal ability of GICs. Furthermore, autophagy abolished the tumorigenicity of CD133 + U87-MG neurosphere cells in an intracranial model. These findings suggest that autophagy regulating GICs self-renewal and tumorigenicity is probably bound up with Notch1 degradation. The results of this study could aid in the design of autophagy-based clinical trials for glioma treatments, which may be of great value.

Highlights

Glioblastomas (GBMs) are the most common and lethal primary central nervous system tumors and have a poor prognosis[1,2]
Flow cytometry was performed to quantify the CD133 + cells in the magnetic-activated cell sorting (MACS) + population to confirm the effectiveness of the sorting
The CD133 + cells were cultured in stem cell medium and formed neurospheres, while cells not sorted on the basis of CD133 positivity failed to develop spheroids under the same culture conditions

Summary

Introduction

Glioblastomas (GBMs) are the most common and lethal primary central nervous system tumors and have a poor prognosis[1,2]. The current standard-of-care treatment consists of maximal surgical resection followed by radiotherapy and subsequent temozolomide treatment. Even with advances in targeted therapies and immunotherapies, the median survival duration of GBM patients is only 14.6 months[3]. I.e., glioma-initiating cells (GICs), which are capable of self-renewal, infinite. The Notch pathway is important in the maintenance of GIC self-renewal and tumorigenicity[6], and the GIC population increases as a result of Notch pathway activation[7]. Our previous study characterized the Notch[1] pathway mediated maintenance of the stem cell phenotype in GBMs8.

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Results

Conclusion