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

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.

Decorin‐mediated inhibition of the migration of U87MG glioma cells involves activation of autophagy and suppression of TGF‐β signaling

“…It suggested that the role of autophagy in the regulation of cell migration possibly mediated by the inhibition of TGF‐β signaling. Previous reports concerning the role of autophagy in glioma cell migration appeared to be controversial . Our results implicated that the regulation of autophagy on cell migration was context dependent, differing with cells types or stimuli.…”

“…It suggested that the role of autophagy in the regulation of cell migration possibly mediated by the inhibition of TGF-b signaling. Previous reports concerning the role of autophagy in glioma cell migration appeared to be controversial [36][37][38].…”

Combination of Endothelial-Monocyte-Activating Polypeptide-II with Temozolomide Suppress Malignant Biological Behaviors of Human Glioblastoma Stem Cells via miR-590-3p/MACC1 Inhibiting PI3K/AKT/mTOR Signal Pathway

“…However, according to other studies, various therapeutic drugs could enhance autophagic cell death in glioblastomas, such as thalidomide (Gao et al, 2009) and vitamin (Bak et al, 2016). Several previous studies suggested that EMAP-II inhibited the cell viability of GSCs via inducing autophagy rather than inducing apoptosis (Ma et al, 2015; Chen et al, 2016). In addition, TMZ-induced autophagy and apoptosis inhibited the cell viability of human glioma cells (Chen et al, 2015; Yu et al, 2015b).…”

“…When combined with thalidomide, a drug could induce autophagy, the cytotoxicity of TMZ to glioma cells was enhanced by autophagy (Gao et al, 2009). Combination of EMAP-II with Rapamycin induces GSCs autophagy and then inhibits the malignant biological behaviors of GSCs (Ma et al, 2015). Therefore, we speculated EMAP-II-induced autophagy might could enhance the antitumor capacity of TMZ.…”

17β-estradiol protects INS-1 insulinoma cells from mitophagy via G protein-coupled estrogen receptors and the PI3K/Akt signaling pathway

“…Inactivation of the PI3K/Akt pathway prevents the translocation of damageregulated autophagy modulator to the mitochondria and induces apoptosis in hepatocellular carcinoma cells by the mediation of mitophagy (41). Furthermore, inhibition of the PI3K/Akt/mTOR signaling pathway is accompanied by autophagy and mitophagy in human glioblastoma cells, glioblastoma stem cells and human prostate cancer (42,43). In the present study, the results indicated that 17β-E2 regulated mitophagy in INS-1 cells through the GPER/PI3K/Akt pathway.…”