Year: 2018
Type: conference-abstract
Abstract: Glioblastoma (GBM) occurs more commonly in males but female GBM patients survive significantly longer. Therefore, understanding the molecular mechanisms that underlie these sex differences may be an innovative approach for developing novel treatments. We found that EGFR amplification and increased mTOR phosphorylation worsen outcome for men, but not women with GBM. To investigate the contribution of the PI3K/mTOR pathway to sex differences in GBM biology and outcome, we used a murine model of GBM with inactivation of Neurofibromin 1 and p53 function, which has previously yielded important insights into sexual dimorphism in GBM. We found that PI3K/mTOR pathway activity was significantly greater in male GBM cells upon treatment with the activating ligands EGF, insulin or IGF-1. Furthermore, when we treated GBM cells with the targeted mTORC1 inhibitor temsirolimus, male GBM cells were significantly more resistant to pathway inhibition, underlining our hypothesis that the PI3K/mTOR pathway is sexually dimorphic in GBM. One mechanism by which the PI3K/mTOR pathway regulates GBM cell growth is through the regulation of metabolic pathways. Furthermore, high expression levels of glycolytic genes worsens outcome in male glioma patients but not females, suggesting there are sex differences in glioma metabolism. To discover sex differences in PI3K/mTOR pathway-regulated metabolism, we performed a targeted metabolomic screen of male and female GBM cells treated either with insulin or vehicle. Multiple central carbon metabolites, involved in nucleotide metabolism, NAD metabolism, and TCA cycle, were significantly different in male and female cells. We further confirmed the validity of these findings with controlled nutrient deprivation and supplementation studies in cell culture and found that male GBM cells were more sensitive to those manipulations. Together, these data indicate that the PI3K/mTOR pathway and its metabolic targets are sexually dimorphic in GBM and that metabolic targeting approaches may be particularly effective in male GBM patients.
Source: Neuro-Oncology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4254509378