Abstract. Glioblastomas are brain tumors with extensive vascularization that are associated with tumor malignancy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is activated in endothelial cell tumors, although its exact function in glioblastoma neovascularization is poorly characterized. The present study identified that endothelial cells derived from human glioblastomas exhibit increased permeability and motility compared with normal brain vascular endothelial cells. Furthermore, the phosphorylation of AKT was significantly induced in glioblastoma-derived endothelial cells and glioblastoma vessels. To the best of our knowledge, the present study demonstrated for the first time that the cell-cell adhesion junction protein Afadin is phosphorylated and re-localized in glioblastoma-derived endothelial cells, and the phosphorylation and re-localization of Afadin is PI3K/AKT pathway-dependent. AKT-mediated phosphorylation and re-localization of Afadin may be critically involved in the modulation of brain endothelial permeability and migration. Therapies targeting the PI3K/AKT/Afadin pathway may therefore be beneficial for reducing the angiogenic potential of glioblastoma.
Background
The Sonic Hedgehog (SHH) signaling pathway plays an important role in various types of human cancers including ovarian cancer; however, its function and underlying mechanism in ovarian cancer are still not entirely understood.
Methods
We detected the expressions of SHH and SQSTM1 in borderline ovarian tumor tissues, epithelial ovarian cancer (EOC) tissues and benign ovarian tumor tissues. Cyclopamine (Cyp, a well‐known inhibitor of SHH signaling pathway) and chloroquine (CQ, the pharmaceutical inhibitor of autophagy) were used in vivo and in vitro (autophagic flux, CCK‐8 assay, wound healing assay, transwell assay, tumor xenograft model). The mechanism of action was explored through Quantitative RT‐PCR and Western Blot.
Results
We found up‐regulation of SHH and accumulation of SQSTM1/P62 in epithelial ovarian cancer. Cyp induced autophagy through the PI3K/AKT signaling pathway. Moreover, low‐dose Cyp and chloroquine (CQ) significantly promoted the migratory ability of SKOV3 cells.
Conclusions
Our findings suggest that inhibition of the SHH pathway and autophagy may be a potential and effective therapy for the treatment of ovarian cancer.
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