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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

The in vivo study of EMAP II and rapamycin. Representative images of mice (A) and tumors (B) obtained from the xenografted mice with or without treatment for 18 weeks. (C) Tumor growth curve in nude mice. (D) Tumor weight in nude mice. ∗∗P < 0.01 vs. control group, #P < 0.05 vs. EMAP-II group, ΔP < 0.05 vs. rapamycin group.
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Figure 9: The in vivo study of EMAP II and rapamycin. Representative images of mice (A) and tumors (B) obtained from the xenografted mice with or without treatment for 18 weeks. (C) Tumor growth curve in nude mice. (D) Tumor weight in nude mice. ∗∗P < 0.01 vs. control group, #P < 0.05 vs. EMAP-II group, ΔP < 0.05 vs. rapamycin group.

Mentions: The growth-inhibitory effects of EMAP-II and rapamycin were further tested in xenografted mice. Representative images of mice and tumors were shown in Figures 9A,B. Tumor growth was significantly suppressed in nude mice treated with EMAP-II, rapamycin or the combination of EMAP II with rapamycin compared with that in the control group (P < 0.01). Combined treatment of EMAP II with rapamycin produced further inhibition on tumor growth than EMAP-II or rapamycin group (P < 0.05) (Figures 9C,D). These results showed that nude mice carrying human GBM cells and GSCs which were treated with the combination of EMAP II with rapamycin produced the smallest tumors.


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)

The in vivo study of EMAP II and rapamycin. Representative images of mice (A) and tumors (B) obtained from the xenografted mice with or without treatment for 18 weeks. (C) Tumor growth curve in nude mice. (D) Tumor weight in nude mice. ∗∗P < 0.01 vs. control group, #P < 0.05 vs. EMAP-II group, ΔP < 0.05 vs. rapamycin group.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 9: The in vivo study of EMAP II and rapamycin. Representative images of mice (A) and tumors (B) obtained from the xenografted mice with or without treatment for 18 weeks. (C) Tumor growth curve in nude mice. (D) Tumor weight in nude mice. ∗∗P < 0.01 vs. control group, #P < 0.05 vs. EMAP-II group, ΔP < 0.05 vs. rapamycin group.
Mentions: The growth-inhibitory effects of EMAP-II and rapamycin were further tested in xenografted mice. Representative images of mice and tumors were shown in Figures 9A,B. Tumor growth was significantly suppressed in nude mice treated with EMAP-II, rapamycin or the combination of EMAP II with rapamycin compared with that in the control group (P < 0.01). Combined treatment of EMAP II with rapamycin produced further inhibition on tumor growth than EMAP-II or rapamycin group (P < 0.05) (Figures 9C,D). These results showed that nude mice carrying human GBM cells and GSCs which were treated with the combination of EMAP II with rapamycin produced the smallest tumors.

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