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.
Highlights
Glioblastoma multiformes (GBMs) are the most malignant and more frequent gliomas
Phosphorylation on ser-2448 is considered predictive of mTOR complex 1 (mTORC1) activation (Navé et al, 1999), whereas phosphorylation on ser-2481 serves as a biomarker for intact mTOR complex 2 (mTORC2) and its sensitivity to rapamycin (Copp et al, 2009)
In the light of accumulating evidence suggesting that the PTEN/PI3K/AKT/mechanistic target of rapamycin (mTOR) pathway is frequently deregulated in GBM and of recent data unveiling its involvement in cancer stem cell maintenance, we have focused our study on the kinase complex mTOR with the purpose to understand the role of mTORC2 in GBM biology compared with PI3K and mTORC1
Summary
Glioblastoma multiformes (GBMs) are the most malignant and more frequent gliomas (about 54% of all astrocytic tumors). The median age of patients at diagnosis is 64 years and the male:female ratio is 1.58:1. GBMs are composed of spindle or rounded cells and typical multinucleated giant cells, whose morphology is extremely immature (Louis et al, 2016). GBMs show high invasiveness and proliferation rate. Despite treatments, GBMs remain an incurable disease and the probability of survival at 5 years is of 9.8% in patients receiving concurrent chemo-radiotherapy and only 1.9% in those treated with radiotherapy alone (Stupp et al, 2005). Depending on specific genetic alterations, glioblastoma are distinct in primary and secondary subtypes with different phenotypic characteristics (Arcuri et al, 2017)
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