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Dual Inhibition of Mek5 and Mek1/2 or Pi3k Pathways Decreases Cell Viability, Proliferation, Migration, and Stemness, and Induces Mesenchymal to Epithelial Transition in Glioblastoma Multiforme | Abstract
Biochemistry & Pharmacology: Open Access

Biochemistry & Pharmacology: Open Access
Open Access

ISSN: 2167-0501

Abstract

Dual Inhibition of Mek5 and Mek1/2 or Pi3k Pathways Decreases Cell Viability, Proliferation, Migration, and Stemness, and Induces Mesenchymal to Epithelial Transition in Glioblastoma Multiforme

Jane E. Cavanaugh

Glioblastoma multiforme (GBM) is an aggressive brain cancer with poor prognosis of less than 15 months. Mitogenactivated protein kinase (MAPK) and phosphatidyl inositol 3-kinase (PI3K) pathways are important regulators of tumor progression, epithelial to mesenchymal transition (EMT), and metastases in GBM. Additionally, epigenetic alterations in histone deacetylase and bromodomain extra-terminal proteins are known to enhance EMT and proliferation in several cancers, including glioblastomas. Our results from bioinformatics analyses of healthy versus GBM tumor samples revealed that there was a significant enrichment in genes involved in EMT and proliferation in GBM versus healthy condition. Moreover, MAPK7, a downstream target of the MAPK pathway, which codes for extracellular signal-regulated kinase (ERK)5 was significantly upregulated in GBM tissues compared to healthy control. The goal of the current research is to develop therapeutic interventions to reverse EMT and proliferation in GBM. Since crosstalk between ERK5 and AKT has been previously noted, we evaluated the effect of single and dual ERK5 and AKT inhibition using known pharmacological inhibitors XMD8-92 and ipatasertib on U87MG cell viability. The effect of novel dual MEK5/PI3K inhibitor on cell proliferation was evaluated in combination with bromodomain 4 (BRD4) inhibitor CPI-203. Moreover, we examined the effect of previously published novel MEK1/2 and/or MEK5 inhibitors on mesenchymal to epithelial transition

Published Date: 2021-06-29; Received Date: 2021-06-08

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