Autophagy Induction by Endothelial-Monocyte Activating Polypeptide II Contributes to the Inhibition of Malignant Biological Behaviors by the Combination of EMAP II with Rapamycin in Human Glioblastoma

Fanjie Meng,Libo Liu,Hao Teng,Lini Zhao,Jun Ma,Shuai Li,Yi Hu,Yunhui Liu,Yixue Xue,Zhuo Xi,Zhen Li,Yilong Yao

doi:10.3389/fnmol.2015.00074

Fanjie Meng, Libo Liu + Show 10 more

Open Access

https://doi.org/10.3389/fnmol.2015.00074

Copy DOI

Abstract

This study aims to investigate the effect of endothelial-monocyte activating polypeptide II (EMAP II) on human glioblastoma (GBM) cells and glioblastoma stem cells (GSCs) as well as its possible mechanisms. In this study, EMAP II inhibited the cell viability and decreased the mitochondrial membrane potential in human GBM cells and GSCs, and autophagy inhibitor 3-methyl adenine (3-MA) blocked these effects. Autophagic vacuoles were formed in these cells after EMAP II treatment and this phenomenon was blocked by 3-MA. In addition, the up-regulation of microtubule-associated protein-1 light chain-3 (LC3)-II and the down-regulation of autophagic degraded substrate p62/SQSTM1 caused by EMAP II were observed. Cells treated with EMAP-II inhibited the PI3K/Akt/mTOR signal pathway, and PI3K/Akt agonist insulin-like growth factor-1 (IGF-1) blocked the effect of EMAP II on the expression of LC3-II and p62/SQSTM1. Cells exposed to EMAP-II experienced mitophagy and ER stress. Furthermore, the inhibition of cell proliferation, migration and invasion of GBM cells and GSCs were more remarkable by the combination of EMAP II and rapamycin than either agent alone in vitro and in vivo. The current study demonstrated that the cytotoxicity of EMAP II in human GBM cells and GSCs was induced by autophagy, accompanied by the inhibition of PI3K/Akt/mTOR signal pathway, mitophagy and ER stress. The combination of EMAP II with rapamycin demonstrated the inhibitory effect on the malignant biological behaviors of human GBM cells and GSCs in vitro and in vivo.

Highlights

Glioblastoma (GBM) is the most common and aggressive human brain tumor characterized by local invasion, microvascular proliferation, and therapeutic resistance (Omuro and DeAngelis, 2013)
We further investigated whether the inhibitory effect of endothelial-monocyte activating polypeptide II (EMAP II) on cell viability was associated with the induced autophagy and apoptosis
We found that low-dose EMAP II inhibited the cell viability and membrane potential (MMP) in human GBM cells and glioblastoma stem cells (GSCs) by inducing autophagy, accompanied by the up-regulation of light chain-3 (LC3)-II and the down-regulation of p62/SQSTM1

Summary

Introduction

Glioblastoma (GBM) is the most common and aggressive human brain tumor characterized by local invasion, microvascular proliferation, and therapeutic resistance (Omuro and DeAngelis, 2013). Considerable evidence have proved that GSCs are responsible for tumor angiogenesis, immune evasion, therapeutic resistance, and tumor recurrence (Bao et al, 2006; Visvader and Lindeman, 2008). Accumulating evidence showed that different manners of programmed cell death could trigger different biological events. Therapeutic studies have shown that glioma cells could undergo autophagy by drugs, which triggers autophagic cell death. Taken together, inducing autophagic death might be one of the main mechanisms of anti-neoplastic drugs in human GBM cells and GSCs

Objectives

Methods

Results

Conclusion