Inhibition of the PI3K but not the MEK/ERK pathway sensitizes human glioma cells to alkylating drugs

Cancer Cell International
Bodo HaasNiels Eckstein

Abstract

Intrinsic chemoresistance of glioblastoma (GBM) is frequently owed to activation of the PI3K and MEK/ERK pathways. These signaling cascades are tightly interconnected however the quantitative contribution of both to intrinsic resistance is still not clear. Here, we aimed at determining the activation status of these pathways in human GBM biopsies and cells and investigating the quantitative impact of both pathways to chemoresistance. Receptor tyrosine kinase (RTK) pathways in temozolomide (TMZ) treatment naive or TMZ resistant human GBM biopsies and GBM cells were investigated by proteome profiling and immunoblotting of a subset of proteins. Resistance to drugs and RTK pathway inhibitors was assessed by MTT assays. Apoptotic rates were determined by Annexin V staining and DNA damage with comet assays and immunoblotting. We analyzed activation of RTK pathways by proteome profiling of tumor samples of patients which were diagnosed a secondary GBM and underwent surgery and patients which underwent a second surgery after TMZ treatment due to recurrence of the tumor. We observed substantial activation of the PI3K and MEK/ERK pathways in both groups. However, AKT and CREB phosphorylation was reduced in biopsies of resistant tumors wh...Continue Reading

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Citations

May 17, 2019·Expert Review of Neurotherapeutics·Diane D McConnellN Scott Litofsky
Sep 1, 2019·International Journal of Molecular Sciences·Synnøve Nymark AasenFrits Thorsen
Dec 20, 2019·Photochemistry and Photobiology·Yan BagloHuang-Chiao Huang
May 6, 2020·Scientific Reports·Karthika D SelvasaravananMike-Andrew Westhoff
Sep 27, 2018·International Journal of Molecular Sciences·Bodo HaasNiels Eckstein
Dec 15, 2020·Journal of Cancer Research and Clinical Oncology·Bodo HaasBernd Kaina
Oct 29, 2020·Biochemical and Biophysical Research Communications·Bakiye Goker BagcaCigir Biray Avci
Jul 3, 2021·International Journal of Molecular Sciences·Maya A DymovaVladimir A Richter
Jul 23, 2021·Journal of Cellular and Molecular Medicine·Shiqi KongZhenzhong Li

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Methods Mentioned

BETA
GTPases
biopsies
FCS
biopsy
Assay
flow cytometry
profiler

Software Mentioned

Prism
Proteome

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