Evaluation of Akt and RICTOR Expression Levels in Astrocytomas of All Grades

Alvarenga, Arthur William; Machado, Luis Eduardo; Rodrigues, Bruna R.; Lupinacci, Fernanda Cristina Sulla; Sanemastu, Paulo; Matta, Eduardo J.; Roffé, Martín; Torres, Luís Fernando Bleggi; Cunha, Isabela Werneck da; Martins, Vilma R.; Hajj, Glaucia Noeli Maroso

doi:10.1369/0022155416675850

Cited by 18 publications

(17 citation statements)

References 41 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More recently, AKT expression and phosphorylation and RICTOR and Ki-67 expression have been evaluated in 195 human astrocytomas of different malignancy degree and 30 healthy controls. This analysis revealed that AKT expression and phosphorylation increases with the histological grade and correlates with a worse overall survival in GBMs, while RICTOR is overexpressed in grade I and II astrocytomas and a shift to a nuclear localization has been demonstrated in GBMs (Alvarenga et al, 2017 ).…”

Section: Introductionmentioning

confidence: 98%

PP242 Counteracts Glioblastoma Cell Proliferation, Migration, Invasiveness and Stemness Properties by Inhibiting mTORC2/AKT

Mecca

Giambanco

Bruscoli

et al. 2018

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is the most malignant brain tumor and is associated with poor prognosis due to its thorny localization, lack of efficacious therapies and complex biology. Among the numerous pathways driving GBM biology studied so far, PTEN/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) signaling plays a pivotal role, as it controls cell survival, proliferation and metabolism and is involved in stem cell maintenance. In front of recent and numerous evidences highlighting mTOR upregulation in GBM, all the strategies developed to inhibit this pathway have been substantially unsuccessful. Our study focused on mTOR complex 2 (mTORC2) to understand its involvement in GBM cell growth, proliferation, migration and invasiveness. We utilized an in vitro model, characterized by various genetic alterations (i.e., GL15, U257, U87MG and U118MG cell lines) in order to achieve the clonal heterogeneity observed in vivo. Additionally, being the U87MG cell line endowed with glioblastoma stem cells (GSCs), we also investigated the role of the PTEN/PI3K/AKT/mTOR pathway in this specific cell population, which is responsible for GBM relapse. We provide further insights that explain the reasons for the failure of numerous clinical trials conducted to date targeting PI3K or mTOR complex 1 (mTORC1) with rapamycin and its analogs. Additionally, we show that mTORC2 might represent a potential clinically valuable target for GBM treatment, as proliferation, migration and GSC maintenance appear to be mTORC2-dependent. In this context, we demonstrate that the novel ATP-competitive mTOR inhibitor PP242 effectively targets both mTORC1 and mTORC2 activation and counteracts cell proliferation via the induction of high autophagy levels, besides reducing cell migration, invasiveness and stemness properties.

show abstract

Section: Introductionmentioning

confidence: 98%

PP242 Counteracts Glioblastoma Cell Proliferation, Migration, Invasiveness and Stemness Properties by Inhibiting mTORC2/AKT

Mecca

Giambanco

Bruscoli

et al. 2018

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…It is clear that the clinical significance of Akt and mTOR are crucial in GBM. Both of them can be used as markers to predict prognosis and target candidates for personalized medicine [ 39 – 42 ]. Their activation promotes cell proliferation, regulates cellular energy metabolism, and provides protection from apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Xihuang Pill Induces Apoptosis of Human Glioblastoma U-87 MG Cells via Targeting ROS-Mediated Akt/mTOR/FOXO1 Pathway

Shao

Yin

et al. 2018

Evidence-Based Complementary and Alternative Medicine

View full text Add to dashboard Cite

Xihuang pill (XHP), a traditional Chinese herbal formula, has long been used as an effective agent against multiple tumors. The aim of this study is to evaluate the effects of XHP on the growth inhibition and apoptosis in glioblastoma U-87 MG cells. Gas chromatography-mass spectrometry (GC-MS) was performed for constituent analysis of XHP. Cell viability, cell cycle arrest, generation of reactive oxygen species (ROS), and apoptosis were measured by CCK-8 assay, PI/RNase staining, DCFH-DA assay, TUNEL assay, Annexin V-FITC/PI double staining, and JC-1 assay, respectively. The role of XHP in the regulation of Akt/mTOR/FOXO1 interaction was clarified by using Western Blotting (WB), immunofluorescence (IF), pharmacological inhibitor or antioxidant, and siRNA silencing. The results suggested that XHP could inhibit U-87 MG cells growth and arrest cells in S-phase cell cycle significantly and that the generation of ROS, collapse of mitochondrial membrane potential, enhancement of Bax/Bcl-xL ratio, and reduction of the precursor forms of caspase-9 and caspase-3 caused by XHP prompted that a ROS-mediated mitochondria-dependent apoptosis was possibly involved. Furthermore, XHP affected the Akt/mTOR/FOXO1 pathway via inhibiting the phosphorylation of Akt, mTOR, and FOXO1 and increasing both prototype and nuclear translocation of FOXO1. Inhibition of Akt, mTOR, and FOXO1 by specific inhibitors or siRNA could interpose the apoptotic induction. In conclusion, we demonstrate for the first time that XHP may regulate glioblastoma U-87 MG cell apoptosis via ROS-mediated Akt/mTOR/FOXO1 pathway.

show abstract

“…In accordance with the in vitro data, these same authors found that the 86% of tumor samples had RICTOR overexpression and 70% of them showed high mTORC2 activity [52] (Table 1). More recently, Alvarenga et al described RICTOR expression and AKT phosphorylation on serine 473 in 195 patients with brain tumors (38 grade I, 49 grade II, 15 grade III, and 93 grade IV astrocytoma) and correlated AKT activation with overall survival (OS) [53]. They did not find any differences in AKT phosphorylation on serine 473 between low-grade glioma and normal brain tissue but they observed a significant increase in AKT phosphorylation in GBM patients compared with normal brain tissue; moreover, the increased expression of activated AKT correlated with a reduced OS [46].…”

Section: Evaluation Of Mtor Activation In Gbm Patientsmentioning

confidence: 99%

Targeting mTOR in Glioblastoma: Rationale and Preclinical/Clinical Evidence

et al. 2018

View full text Add to dashboard Cite

The mechanistic target of rapamycin (mTOR) drives several physiologic and pathologic cellular processes and is frequently deregulated in different types of tumors, including glioblastoma (GBM). Despite recent advancements in understanding the molecular mechanisms involved in GBM biology, the survival rates of this tumor are still disappointing, primarily due to the lack of efficacious treatments. The phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway has emerged as a crucial player in GBM development and progression. However, to date, all the attempts to target this pathway with PI3K, AKT, or mTORC1 inhibitors failed to improve the outcome of patients with GBM. Despite these discouraging results, recent evidence pointed out that the blockade of mTORC2 might provide a useful therapeutic strategy for GBM, with the potential to overcome the limitations that mTORC1 inhibitors have shown so far. In this review, we analyzed the rationale of targeting mTOR in GBM and the available preclinical and clinical evidence supporting the choice of this therapeutic approach, highlighting the different roles of mTORC1 and mTORC2 in GBM biology.

show abstract

Evaluation of Akt and RICTOR Expression Levels in Astrocytomas of All Grades

Cited by 18 publications

References 41 publications

PP242 Counteracts Glioblastoma Cell Proliferation, Migration, Invasiveness and Stemness Properties by Inhibiting mTORC2/AKT

PP242 Counteracts Glioblastoma Cell Proliferation, Migration, Invasiveness and Stemness Properties by Inhibiting mTORC2/AKT

Xihuang Pill Induces Apoptosis of Human Glioblastoma U-87 MG Cells via Targeting ROS-Mediated Akt/mTOR/FOXO1 Pathway

Targeting mTOR in Glioblastoma: Rationale and Preclinical/Clinical Evidence

Contact Info

Product

Resources

About