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 in vitro tube formation of GECs, which are critical for angiogenesis. Taken together, we have demonstrated the fact that
EMAP II resulted in the decreased GBM-induced angiogenesis by inducing autophagy, which might contribute to establishing potential strategies for human GBM treatment.