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

Abstract

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.

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity

“…5). This is in line with previous research showing that upregulation of αKG-dependent Gln metabolism and increased GLS expression promotes the maintenance of cancer stem cells through various mechanisms 26,[62][63][64][65] . Furthermore, Gln metabolism promotes the maintenance of stemness through elevating the synthesis of GSH and maintenance of a balanced redox homeostasis 23,66,67 .…”

Probing Internalization Effects and Biocompatibility of Ultrasmall Zirconium Metal-Organic Frameworks UiO-66 NP in U251 Glioblastoma Cancer Cells

“…Invasiveness is considered as a major determinant for malignant behavior in human gliomas and U251 cells represent a highly invasive tumor [ 38 ]. For this reason, the involvement of UiO-66_N in influencing migration properties was investigated.…”

Therapeutic Potential of Autophagy in Glioblastoma Treatment With Phosphoinositide 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin Signaling Pathway Inhibitors

“…For instance, GDC-0941, a highly specific PI3K inhibitor, when combined with TMZ and ionizing radiation (IR), enhances the autophagy response and proapoptotic effects, leading to suppressed cell viability in GB cell lines ( 9 ). Mecca et al reported that PP242 represses GB cell proliferation through induction of high autophagy levels and reduction of cell migration and invasiveness ( 71 ). Choi et al found that treatment with a dual inhibitor of PI3K/mTOR PI-103 increased the cytotoxic and sensitive effects of radiation therapy plus TMZ in GB cells.…”