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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.

Ma J, Meng F, Li S, Liu L, Zhao L, Liu Y, Hu Y, Li Z, Yao Y, Xi Z, Teng H, Xue Y - Front Mol Neurosci (2015)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University Shenyang, China ; Institute of Pathology and Pathophysiology, China Medical University Shenyang, China.

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.

No MeSH data available.


Related in: MedlinePlus

Effects of EMAP II and tauroursodeoxycholate (TUDC) on the expression of UPR-related proteins in human GBM cells and GSCs. Western blot analysis of the expression of GRP78, p-eIF2α, eIF2α, and CHOP in U87 (A), U118 (B), and GSCs (C) after treatment with EMAP II, TUDC and their combination. Values represented the means ± SD (n = 5, each). ∗P < 0.05 and ∗∗P < 0.01 vs. control group, ##P < 0.01 vs. EMAP II group.
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Figure 7: Effects of EMAP II and tauroursodeoxycholate (TUDC) on the expression of UPR-related proteins in human GBM cells and GSCs. Western blot analysis of the expression of GRP78, p-eIF2α, eIF2α, and CHOP in U87 (A), U118 (B), and GSCs (C) after treatment with EMAP II, TUDC and their combination. Values represented the means ± SD (n = 5, each). ∗P < 0.05 and ∗∗P < 0.01 vs. control group, ##P < 0.01 vs. EMAP II group.

Mentions: Several studies reported that autophagy could be induced by unfolded protein response (UPR) which is the major endoplasmic reticulum (ER) stress pathway (Tsai and Weissman, 2010). To examine whether ER stress was induced by the EMAP-II treatment, levels of the UPR-related proteins GRP78, p-eIF2α, eIF2α, and CHOP were measured after cells treated with 0.05 nM EMAP II for 0.5 h, (TUDC, an ER stress inhibitor) or their combination. As shown in Figure 7A, the expression of GRP78, p-eIF2α, and CHOP were increased in EMAP II group compared with the control group in U87 cells (P < 0.01). In addition, the expression of GRP78, p-eIF2α, and CHOP were decreased in the combination of EMAP II with TUDC group compared with the EMAP II group (P < 0.01). The similar results were also observed in U118 cells and GSCs (Figures 7B,C). These results suggested that human GBM cells and GSCs exposed to EMAP-II experienced ER stress.


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.

Ma J, Meng F, Li S, Liu L, Zhao L, Liu Y, Hu Y, Li Z, Yao Y, Xi Z, Teng H, Xue Y - Front Mol Neurosci (2015)

Effects of EMAP II and tauroursodeoxycholate (TUDC) on the expression of UPR-related proteins in human GBM cells and GSCs. Western blot analysis of the expression of GRP78, p-eIF2α, eIF2α, and CHOP in U87 (A), U118 (B), and GSCs (C) after treatment with EMAP II, TUDC and their combination. Values represented the means ± SD (n = 5, each). ∗P < 0.05 and ∗∗P < 0.01 vs. control group, ##P < 0.01 vs. EMAP II group.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4664732&req=5

Figure 7: Effects of EMAP II and tauroursodeoxycholate (TUDC) on the expression of UPR-related proteins in human GBM cells and GSCs. Western blot analysis of the expression of GRP78, p-eIF2α, eIF2α, and CHOP in U87 (A), U118 (B), and GSCs (C) after treatment with EMAP II, TUDC and their combination. Values represented the means ± SD (n = 5, each). ∗P < 0.05 and ∗∗P < 0.01 vs. control group, ##P < 0.01 vs. EMAP II group.
Mentions: Several studies reported that autophagy could be induced by unfolded protein response (UPR) which is the major endoplasmic reticulum (ER) stress pathway (Tsai and Weissman, 2010). To examine whether ER stress was induced by the EMAP-II treatment, levels of the UPR-related proteins GRP78, p-eIF2α, eIF2α, and CHOP were measured after cells treated with 0.05 nM EMAP II for 0.5 h, (TUDC, an ER stress inhibitor) or their combination. As shown in Figure 7A, the expression of GRP78, p-eIF2α, and CHOP were increased in EMAP II group compared with the control group in U87 cells (P < 0.01). In addition, the expression of GRP78, p-eIF2α, and CHOP were decreased in the combination of EMAP II with TUDC group compared with the EMAP II group (P < 0.01). The similar results were also observed in U118 cells and GSCs (Figures 7B,C). These results suggested that human GBM cells and GSCs exposed to EMAP-II experienced ER stress.

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University Shenyang, China ; Institute of Pathology and Pathophysiology, China Medical University Shenyang, China.

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.

No MeSH data available.


Related in: MedlinePlus