GPER Agonist G-1 Disrupts Tubulin Dynamics and Potentiates Temozolomide to Impair Glioblastoma Cell Proliferation.

Alex Hirtz,Fabien Rech,Nolwenn Lebourdais,Hélène Dubois-Pot-Schneider,Yann Bailly,Athénaïs Vaginay,Hélène Dumond,Malika Smaïl-Tabbone

doi:10.3390/cells10123438

Abstract

Glioblastoma (GBM) is the most common brain tumor in adults, which is very aggressive, with a very poor prognosis that affects men twice as much as women, suggesting that female hormones (estrogen) play a protective role. With an in silico approach, we highlighted that the expression of the membrane G-protein-coupled estrogen receptor (GPER) had an impact on GBM female patient survival. In this context, we explored for the first time the role of the GPER agonist G-1 on GBM cell proliferation. Our results suggested that G-1 exposure had a cytostatic effect, leading to reversible G2/M arrest, due to tubulin polymerization blockade during mitosis. However, the observed effect was independent of GPER. Interestingly, G-1 potentiated the efficacy of temozolomide, the current standard chemotherapy treatment, since the combination of both treatments led to prolonged mitotic arrest, even in a temozolomide less-sensitive cell line. In conclusion, our results suggested that G-1, in combination with standard chemotherapy, might be a promising way to limit the progression and aggressiveness of GBM.

Highlights

Accepted: 3 December 2021Gliomas are one of the most common groups of primary brain tumors of the central nervous system (CNS) in adults
Exploration of the GBM project from TCGA database indicated that G-protein-coupled estrogen receptor (GPER) expression was predictive of overall survival in patients who underwent radiochemotherapy treatment (Figure 1a), but not in the whole patient population
GPER expression was significantly of good prognosis for female GBM patients (Figure 1b). Since this finding was not observed for male patients, this could indicate that GPER was differently expressed between both sexes

Summary

Introduction

Gliomas are one of the most common groups of primary brain tumors of the central nervous system (CNS) in adults. Their classification is based on a combination of histological and molecular features for prognostic purposes [1]. The grades range from 1 to 4: grade 4 designating glioblastoma (GBM), IDH-wildtype, which are fast-growing tumors with anaplastic foci [2]. Their incidence, constantly increasing, is estimated at 6/105. Most tumor recurrences occur within a few months in the excision margins of the irradiated volume, and lead to death within

Methods

Results

Conclusion