Celastrol Suppresses Glioma Vasculogenic Mimicry Formation and Angiogenesis by Blocking the PI3K/Akt/mTOR Signaling Pathway

Abstract

Angiogenesis and vasculogenic mimicry (VM) are thought to be the predominant processes ensuring tumor blood supply during the growth and metastasis of glioblastoma (GBM). Celastrol has potential anti-glioma effects, however the mechanisms underlying these effects remain unclarified. Recent studies have shown that the PI3K/Akt/mTOR signaling pathway is closely related to angiogenesis and VM formation. In the present study, we have demonstrated, for the first time, that celastrol eliminated VM formation by blocking this signaling pathway in glioma cells. By the treatment of celastrol, tumor growth was suppressed, tight junction and basal lamina structures in tumor microvasculature were disarranged in U87 glioma orthotopic xenografts in nude mice. Periodic acid Schiff (PAS)-CD31 staining revealed that celastrol inhibited both VM and angiogenesis in tumor tissues. Additionally, celastrol reduced the expression levels of the angiogenesis-related proteins CD31, vascular endothelial growth factor receptor (VEGFR) 2, angiopoietin (Ang) 2 and VEGFA, VM-related proteins ephrin type-A receptor (EphA) 2, and vascular endothelial (VE)-cadherin. Hypoxia inducible factor (HIF)-1a, phosphorylated PI3K, Akt, and mTOR were also downregulated by treatment with celastrol. In vitro, we further demonstrated that celastrol inhibited the growth, migration, and invasion of U87 and U251 cells, disrupted VM formation, and blocked the activity of PI3K, Akt, and mTOR. Collectively, our data suggest that celastrol inhibits VM formation and angiogenesis likely by regulating the PI3K/Akt/mTOR signaling pathway.

<p>Cytotoxic and Antiproliferative Effects of β-Mangostin on Rat C6 Glioma Cells Depend on Oxidative Stress Induction via PI3K/AKT/mTOR Pathway Inhibition</p>

“…28,29 Dysregulation of this pathway is also related to the therapeutic resistance of glioma. 30 With that, our results demonstrated that β-mangostin resulted in a significant induction of apoptosis and in a concomitant reduction of Akt phosphorylation at Ser473, which consequently inhibited PI3K/AKT/mTOR signaling pathway in C6 cells. In addition, flow cytometry analysis indicated that treatment of C6 cells with β-mangostin resulted in a significant induction of apoptosis.…”

The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment

“…Recently, it is demonstrated that celastrol, an anti-glioma medicine, downregulated the HIF-1α, blocked the PI3K/Akt/mTOR signaling and disrupted angiogenesis and VM formation. [ 340 ]. mTOR, a downstream mediator in PI3K/AKT pathway, complicatedly regulated by HIF-1α signaling and acts as a nutrient/hypoxia sensor to modulate protein synthesis.…”

Long Non-coding RNA IRAIN Inhibits VEGFA Expression via Enhancing Its DNA Methylation Leading to Tumor Suppression in Renal Carcinoma

“…More importantly, previous studies have pointed out the significance of methylation levels at the paraoxonase 1 (PON1) and forkhead box protein M1 (FOXM1) promoter regions to the progression and development of RC ( 42 , 43 ), highly suggestive of the potential regulatory function of lncRNA IRAIN in the progression and development of RC involving other protein targets like PON1 and FOXM1. Also, VEGFA has been recognized to participate in tumorigenesis by mediating angiogenesis ( 44 , 45 ), yet we focused on the regulatory role of VEGFA in RC cell survival, migration, and invasion, underscoring the various forms of regulation of VEGFA in RC, which requires further investigation in the future. However, given the mounting evidence regarding the aberrant expression of VEGFA in RC ( 40 , 46 ), treatment modalities involving antibodies against VEGFA may hold therapeutic promise for RC management.…”