PI3K/AKT/Afadin signaling pathway contributes to pathological vascularization in glioblastomas

Abstract

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.

Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling

“…14G-L). Consistent with previous reports in the literature [27][28][29]44,45 we find that p-AKT and p-ERK1/2 are more strongly activated in tumor-associated blood vessels than in the surrounding tumor tissue, although longer-exposure images confirm that p-AKT and p-ERK1/2 are indeed also present in the surrounding tumor cells ( Supplementary Fig. 14M, N).…”

“…However, the ability of tumors to overproduce pro-angiogenic ligands and overcome targeted therapies has hampered this approach to date 25,26 . An alternative way to circumvent this problem is to target the re-synthesis of critical signaling substrates, like phosphoinositides, that are consumed during intracellular transduction of pro-angiogenic signals in ECs, thereby harnessing the tumor's own production of excess stimulatory ligands to deplete adjacent host ECs of the capacity to respond to these signals 1,13,14,16,[27][28][29] .…”

Afadin (AF6) in cancer progression: A multidomain scaffold protein with complex and contradictory roles

“…Thus, phosphorylation of afadin by Akt promotes relocalization of afadin from the membrane to the nucleus, which disrupts AJs and results in increased cell migration in breast cancer. [ 125,126 ] Nuclear localization of afadin, which was associated with increased migration, is greater in invasive breast cancer. [ 125 ] This was also demonstrated in endothelial cells present within glioblastomas, where a decrease in membrane‐localized afadin and an increase of afadin within the nucleus was observed.…”

“…[ 125 ] This was also demonstrated in endothelial cells present within glioblastomas, where a decrease in membrane‐localized afadin and an increase of afadin within the nucleus was observed. [ 126 ] Inhibition of this Akt‐mediated phosphorylation event results in reduced endothelial cell migration and may also affect permeability and angiogenesis. [ 126 ]…”

“…[ 126 ] Inhibition of this Akt‐mediated phosphorylation event results in reduced endothelial cell migration and may also affect permeability and angiogenesis. [ 126 ]…”