Endothelial-Monocyte Activating Polypeptide II Suppresses the

The obstacle in delivering therapeutics to glioblastoma (GBM) is tumor-induced angiogenesis which leads to the formation of abnormal vessels and a dysfunctional blood-tumor barrier. Here, we elucidated the effect of endothelial-monocyte activating polypeptide II (EMAP II) on the GBM-induced angiogenesis as well as its potential mechanisms. Our results proved that EMAP II inhibited the viability, mitochondrial membrane potential, migration and tube formation of GBM-induced endothelial cells (GECs) by inducing cell autophagy, demonstrated by cell viability assay, JC-1 staining assay, transwell assay and tube formation assay, respectively. Cell autophagy was induced by EMAP II through the observation of autophagic vacuoles formation and the up-regulation of microtubule-associated protein-1 light chain-3 (LC3)-II and p62/SQSTM1 expression, demonstrated by transmission electron microscopy analysis, immunofluorescence assay and Western blot assay. The activity of PI3K/AKT/mTOR signal pathway could be inhibited by the EMAP II treatment. Furthermore, unfolded protein response (UPR)-related proteins (GRP78, eIF2α, and CHOP) were up-regulated by EMAP II, which suggest that GECs exposed to EMAP II experienced endoplasmic reticulum stress. Further, mechanistic investigations found that EMAP II reduced the miR-96 expression which could directly target the 3'-UTR of these UPR-related proteins, and over-expression of miR-96 inhibited LC3 and p62/SQSTM1 expression by down-regulating these UPR-related proteins in GECs. Moreover, the combination of EMAP II with miR-96 inhibitor showed the inhibitory effect on the viability, migration, and