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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 rapamycin on the cell proliferation, migration, and invasion of human GBM cells and GSCs. (A) Cell proliferation of U87, U118, and GSCs was assessed by CCK8 assay. (B) The migration of U87 and U118 cells was measured by wound healing assay. (C) Cell migration of U87, U118, and GSCs was measured by transwell assay. (D) Cell invasion of U87, U118, and GSCs was measured by transwell assay. Values represented the means ± SD (n = 5, each). ∗∗P < 0.01 vs. control group; #P < 0.05 vs. EMAP II group; ΔP < 0.05 vs. rapamycin group.
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Figure 8: Effects of EMAP II and rapamycin on the cell proliferation, migration, and invasion of human GBM cells and GSCs. (A) Cell proliferation of U87, U118, and GSCs was assessed by CCK8 assay. (B) The migration of U87 and U118 cells was measured by wound healing assay. (C) Cell migration of U87, U118, and GSCs was measured by transwell assay. (D) Cell invasion of U87, U118, and GSCs was measured by transwell assay. Values represented the means ± SD (n = 5, each). ∗∗P < 0.01 vs. control group; #P < 0.05 vs. EMAP II group; ΔP < 0.05 vs. rapamycin group.

Mentions: The abilities of cell proliferation, migration and invasion were investigated to further evaluate the effects of the combination of EMAP II with rapamycin on the biological behaviors of human GBM cells and GSCs. As shown in Figure 8A, compared with the control group, the cell proliferation of U87, U118, and GSCs were inhibited after EMAP II or rapamycin treatment (P < 0.01). The cell proliferation of U87, U118, and GSCs was more remarkably inhibited by the combination of EMAP II with rapamycin compared with the use of either agent alone (P < 0.05). As shown in Figure 8B, scratch wound healing assay showed that the migration of U87 and U118 cells in EMAP II or rapamycin groups were inhibited compared with that in the control group (P < 0.01). In addition, EMAP II in combination with rapamycin displayed even greater inhibitory effect on the migration of U87 and U118 cells than either EMAP II or rapamycin alone (P < 0.05). Subsequently, we employed the transwell migration assay to further define the migration of U87, U118 and GSCs, and the results were similar as above (Figure 8C). As shown in Figure 8D, the invasion of U87, U118, and GSCs in EMAP II or rapamycin groups were inhibited compared with that in the control group (P < 0.01). EMAP II in combination with rapamycin displayed even greater inhibitory effect on the invasion of U87, U118, and GSCs than either EMAP II or rapamycin alone (P < 0.05). The above results suggested that the combination of EMAP II with rapamycin inhibited the malignant biological behaviors of human GBM cells and GSCs.


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 rapamycin on the cell proliferation, migration, and invasion of human GBM cells and GSCs. (A) Cell proliferation of U87, U118, and GSCs was assessed by CCK8 assay. (B) The migration of U87 and U118 cells was measured by wound healing assay. (C) Cell migration of U87, U118, and GSCs was measured by transwell assay. (D) Cell invasion of U87, U118, and GSCs was measured by transwell assay. Values represented the means ± SD (n = 5, each). ∗∗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 8: Effects of EMAP II and rapamycin on the cell proliferation, migration, and invasion of human GBM cells and GSCs. (A) Cell proliferation of U87, U118, and GSCs was assessed by CCK8 assay. (B) The migration of U87 and U118 cells was measured by wound healing assay. (C) Cell migration of U87, U118, and GSCs was measured by transwell assay. (D) Cell invasion of U87, U118, and GSCs was measured by transwell assay. Values represented the means ± SD (n = 5, each). ∗∗P < 0.01 vs. control group; #P < 0.05 vs. EMAP II group; ΔP < 0.05 vs. rapamycin group.
Mentions: The abilities of cell proliferation, migration and invasion were investigated to further evaluate the effects of the combination of EMAP II with rapamycin on the biological behaviors of human GBM cells and GSCs. As shown in Figure 8A, compared with the control group, the cell proliferation of U87, U118, and GSCs were inhibited after EMAP II or rapamycin treatment (P < 0.01). The cell proliferation of U87, U118, and GSCs was more remarkably inhibited by the combination of EMAP II with rapamycin compared with the use of either agent alone (P < 0.05). As shown in Figure 8B, scratch wound healing assay showed that the migration of U87 and U118 cells in EMAP II or rapamycin groups were inhibited compared with that in the control group (P < 0.01). In addition, EMAP II in combination with rapamycin displayed even greater inhibitory effect on the migration of U87 and U118 cells than either EMAP II or rapamycin alone (P < 0.05). Subsequently, we employed the transwell migration assay to further define the migration of U87, U118 and GSCs, and the results were similar as above (Figure 8C). As shown in Figure 8D, the invasion of U87, U118, and GSCs in EMAP II or rapamycin groups were inhibited compared with that in the control group (P < 0.01). EMAP II in combination with rapamycin displayed even greater inhibitory effect on the invasion of U87, U118, and GSCs than either EMAP II or rapamycin alone (P < 0.05). The above results suggested that the combination of EMAP II with rapamycin inhibited the malignant biological behaviors of human GBM cells and GSCs.

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