PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells

Glioblastoma (GBM) is the most lethal primary brain cancer that lacks effective molecular targeted therapies. The PI3K/AKT/mTOR pathway is activated in 90% of all Glioblastoma multiforme (GBM) tumors. To gain insight into the impact of the PI3K pathway on GBM metabolism, we treated U87MG GBM cells w...

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Autores principales:	Shreya Udawant, Carl Litif, Alma Lopez, Bonnie Gunn, Erin Schuenzel, Megan Keniry
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	glioblastoma (GBM) PI3K/AKT/mTOR pathway glycolysis RNA-seq Gene Set Enrichment Analysis (GSEA) Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/528c0c2447e74815883efe86d2adce03
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spelling	oai:doaj.org-article:528c0c2447e74815883efe86d2adce032021-11-25T17:11:02ZPI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells10.3390/cells101130652073-4409https://doaj.org/article/528c0c2447e74815883efe86d2adce032021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3065https://doaj.org/toc/2073-4409Glioblastoma (GBM) is the most lethal primary brain cancer that lacks effective molecular targeted therapies. The PI3K/AKT/mTOR pathway is activated in 90% of all Glioblastoma multiforme (GBM) tumors. To gain insight into the impact of the PI3K pathway on GBM metabolism, we treated U87MG GBM cells with NVP-BEZ235 (PI3K and mTOR a dual inhibitor) and identified differentially expressed genes with RNA-seq analysis. RNA-seq identified 7803 differentially regulated genes in response to NVP-BEZ235. Gene Set Enrichment Analysis (GSEA) identified two glycolysis-related gene sets that were significantly enriched (<i>p <</i> 0.05) in control samples compared to NVP-BEZ235-treated samples. We validated the inhibition of glycolytic genes by NVP-BEZ235 and examined the impact of the FOXO1 inhibitor (AS1842856) on these genes in a set of GBM cell lines. FOXO1 inhibition alone was associated with reduced <i>LDHA</i> expression, but not <i>ENO1</i> or <i>PKM2</i>. Bioinformatics analyses revealed that PI3K-impacted glycolytic genes were over-expressed and co-expressed in GBM clinical samples. The elevated expression of PI3K-impacted glycolytic genes was associated with poor prognosis in GBM based on Kaplan–Meier survival analyses. Our results suggest novel insights into hallmark metabolic reprogramming associated with the PI3K-mTOR dual inhibition.Shreya UdawantCarl LitifAlma LopezBonnie GunnErin SchuenzelMegan KeniryMDPI AGarticleglioblastoma (GBM)PI3K/AKT/mTOR pathwayglycolysisRNA-seqGene Set Enrichment Analysis (GSEA)Biology (General)QH301-705.5ENCells, Vol 10, Iss 3065, p 3065 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	glioblastoma (GBM) PI3K/AKT/mTOR pathway glycolysis RNA-seq Gene Set Enrichment Analysis (GSEA) Biology (General) QH301-705.5
spellingShingle	glioblastoma (GBM) PI3K/AKT/mTOR pathway glycolysis RNA-seq Gene Set Enrichment Analysis (GSEA) Biology (General) QH301-705.5 Shreya Udawant Carl Litif Alma Lopez Bonnie Gunn Erin Schuenzel Megan Keniry PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells
description	Glioblastoma (GBM) is the most lethal primary brain cancer that lacks effective molecular targeted therapies. The PI3K/AKT/mTOR pathway is activated in 90% of all Glioblastoma multiforme (GBM) tumors. To gain insight into the impact of the PI3K pathway on GBM metabolism, we treated U87MG GBM cells with NVP-BEZ235 (PI3K and mTOR a dual inhibitor) and identified differentially expressed genes with RNA-seq analysis. RNA-seq identified 7803 differentially regulated genes in response to NVP-BEZ235. Gene Set Enrichment Analysis (GSEA) identified two glycolysis-related gene sets that were significantly enriched (<i>p <</i> 0.05) in control samples compared to NVP-BEZ235-treated samples. We validated the inhibition of glycolytic genes by NVP-BEZ235 and examined the impact of the FOXO1 inhibitor (AS1842856) on these genes in a set of GBM cell lines. FOXO1 inhibition alone was associated with reduced <i>LDHA</i> expression, but not <i>ENO1</i> or <i>PKM2</i>. Bioinformatics analyses revealed that PI3K-impacted glycolytic genes were over-expressed and co-expressed in GBM clinical samples. The elevated expression of PI3K-impacted glycolytic genes was associated with poor prognosis in GBM based on Kaplan–Meier survival analyses. Our results suggest novel insights into hallmark metabolic reprogramming associated with the PI3K-mTOR dual inhibition.
format	article
author	Shreya Udawant Carl Litif Alma Lopez Bonnie Gunn Erin Schuenzel Megan Keniry
author_facet	Shreya Udawant Carl Litif Alma Lopez Bonnie Gunn Erin Schuenzel Megan Keniry
author_sort	Shreya Udawant
title	PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells
title_short	PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells
title_full	PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells
title_fullStr	PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells
title_full_unstemmed	PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells
title_sort	pi3k pathway inhibition with nvp-bez235 hinders glycolytic metabolism in glioblastoma multiforme cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/528c0c2447e74815883efe86d2adce03
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PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells

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