P04.54  High Dose Progesterone Induces Growth Inhibition in Human U87 and A172 Glioblastoma Cell With Concomitant Changes in Mitochondrial and Cytoskeleton Proteins

Altinöz, Meriç A.; Yilmaz, M; Uçal, Yasemin; Özpınar, Aysel; Başkan, Özdil; Elmacı, İlhan

doi:10.1093/neuonc/noy139.288

Cited by 1 publication

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“…Progesterone, on the other hand, can indirectly modulate estrogen production by interfering with estrogen receptor activity or releasing gonadotropins through feedback mechanisms [61]. Despite producing pro-tumorigenic effects at low doses, high doses of progesterone have demonstrated therapeutic effects against GBM by downregulating the activity of progesterone receptor B (PR-B), a protein that promotes tumor cell growth, or through alteration of detoxification mechanisms, stress, immune response, and glucose metabolism [62][63][64][65][66][67]. Furthermore, a significant decrease in the expression levels of EGFR, Akt, phospho-Akt, mTOR, and phospho-mTOR has been observed following high doses of progesterone, indicating its potential attenuating effect against GBM through the PI3K/Akt and metabolic pathways [68][69][70].…”

Section: Signature-based Drug Repurposingmentioning

confidence: 99%

Modular Hub Genes in DNA Microarray Suggest Potential Signaling Pathway Interconnectivity in Various Glioma Grades

Orda,

Fowler,

Tayo

2024

Biology

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Gliomas have displayed significant challenges in oncology due to their high degree of invasiveness, recurrence, and resistance to treatment strategies. In this work, the key hub genes mainly associated with different grades of glioma, which were represented by pilocytic astrocytoma (PA), oligodendroglioma (OG), anaplastic astrocytoma (AA), and glioblastoma multiforme (GBM), were identified through weighted gene co-expression network analysis (WGCNA) of microarray datasets retrieved from the Gene Expression Omnibus (GEO) database. Through this, four highly correlated modules were observed to be present across the PA (GSE50161), OG (GSE4290), AA (GSE43378), and GBM (GSE36245) datasets. The functional annotation and pathway enrichment analysis done through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) showed that the modules and hub genes identified were mainly involved in signal transduction, transcription regulation, and protein binding, which collectively deregulate several signaling pathways, mainly PI3K/Akt and metabolic pathways. The involvement of several hub genes primarily linked to other signaling pathways, including the cAMP, MAPK/ERK, Wnt/β-catenin, and calcium signaling pathways, indicates potential interconnectivity and influence on the PI3K/Akt pathway and, subsequently, glioma severity. The Drug Repurposing Encyclopedia (DRE) was used to screen for potential drugs based on the up- and downregulated hub genes, wherein the synthetic progestin hormones norgestimate and ethisterone were the top drug candidates. This shows the potential neuroprotective effect of progesterone against glioma due to its influence on EGFR expression and other signaling pathways. Aside from these, several experimental and approved drug candidates were also identified, which include an adrenergic receptor antagonist, a PPAR-γ receptor agonist, a CDK inhibitor, a sodium channel blocker, a bradykinin receptor antagonist, and a dopamine receptor agonist, which further highlights the gene network as a potential therapeutic avenue for glioma.

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