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

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2021 Dec 24

PMID 34943948

Citations 9

Authors

Alex Hirtz

Nolwenn Lebourdais

Fabien Rech

Yann Bailly

Athenais Vaginay

Malika Smail-Tabbone

Helene Dubois-Pot-Schneider

Helene Dumond

Affiliations

Soon will be listed here.

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.

Citing Articles

G protein-coupled estrogen receptor 1 and collagen XVII endodomain expression in human cutaneous melanomas: can they serve as prognostic factors?.

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The G Protein-Coupled Estrogen Receptor (GPER): A Critical Therapeutic Target for Cancer.

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GPER1 Activation Exerts Anti-Tumor Activity in Multiple Myeloma.

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The GPER Agonist LNS8801 Induces Mitotic Arrest and Apoptosis in Uveal Melanoma Cells.

Ambrosini G, Natale C, Musi E, Garyantes T, Schwartz G Cancer Res Commun. 2023; 3(4):540-547.

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Molecular Characterization of the Dual Effect of the GPER Agonist G-1 in Glioblastoma.

Hirtz A, Bailly Y, Rech F, Pierson J, Dumond H, Dubois-Pot-Schneider H Int J Mol Sci. 2022; 23(22).

PMID: 36430793 PMC: 9695951. DOI: 10.3390/ijms232214309.

References

Zhang Z, Qin P, Deng Y, Ma Z, Guo H, Guo H . The novel estrogenic receptor GPR30 alleviates ischemic injury by inhibiting TLR4-mediated microglial inflammation. J Neuroinflammation. 2018; 15(1):206. PMC: 6043971. DOI: 10.1186/s12974-018-1246-x. View

Dennis M, Field A, Burai R, Ramesh C, Petrie W, Bologa C . Identification of a GPER/GPR30 antagonist with improved estrogen receptor counterselectivity. J Steroid Biochem Mol Biol. 2011; 127(3-5):358-66. PMC: 3220788. DOI: 10.1016/j.jsbmb.2011.07.002. View

Chimento A, De Luca A, Nocito M, Avena P, Padula D, Zavaglia L . Role of GPER-Mediated Signaling in Testicular Functions and Tumorigenesis. Cells. 2020; 9(9). PMC: 7563107. DOI: 10.3390/cells9092115. View

Pupo M, Bodmer A, Berto M, Maggiolini M, Dietrich P, Picard D . A genetic polymorphism repurposes the G-protein coupled and membrane-associated estrogen receptor GPER to a transcription factor-like molecule promoting paracrine signaling between stroma and breast carcinoma cells. Oncotarget. 2017; 8(29):46728-46744. PMC: 5564519. DOI: 10.18632/oncotarget.18156. View

Han Z, Chang Y, Zhou Y, Zhang H, Chen L, Zhang Y . GPER agonist G1 suppresses neuronal apoptosis mediated by endoplasmic reticulum stress after cerebral ischemia/reperfusion injury. Neural Regen Res. 2019; 14(7):1221-1229. PMC: 6425826. DOI: 10.4103/1673-5374.251571. View

Thiebaut C, Chamard-Jovenin C, Chesnel A, Morel C, Djermoune E, Boukhobza T . Mammary epithelial cell phenotype disruption in vitro and in vivo through ERalpha36 overexpression. PLoS One. 2017; 12(3):e0173931. PMC: 5354400. DOI: 10.1371/journal.pone.0173931. View

Koganti S, Snyder R, Gumaste U, Karamyan V, Thekkumkara T . 2-methoxyestradiol binding of GPR30 down-regulates angiotensin AT(1) receptor. Eur J Pharmacol. 2013; 723:131-40. PMC: 3946276. DOI: 10.1016/j.ejphar.2013.10.064. View

Kim J, Szinte J, Boulware M, Frick K . 17β-Estradiol and Agonism of G-protein-Coupled Estrogen Receptor Enhance Hippocampal Memory via Different Cell-Signaling Mechanisms. J Neurosci. 2016; 36(11):3309-21. PMC: 4792941. DOI: 10.1523/JNEUROSCI.0257-15.2016. View

Ariazi E, Brailoiu E, Yerrum S, Shupp H, Slifker M, Cunliffe H . The G protein-coupled receptor GPR30 inhibits proliferation of estrogen receptor-positive breast cancer cells. Cancer Res. 2010; 70(3):1184-94. PMC: 2879282. DOI: 10.1158/0008-5472.CAN-09-3068. View

10.

Xu Y, Shen M, Li Y, Sun Y, Teng Y, Wang Y . The synergic antitumor effects of paclitaxel and temozolomide co-loaded in mPEG-PLGA nanoparticles on glioblastoma cells. Oncotarget. 2016; 7(15):20890-901. PMC: 4991499. DOI: 10.18632/oncotarget.7896. View

11.

Harmalkar M, Upraity S, Kazi S, Shirsat N . Tamoxifen-Induced Cell Death of Malignant Glioma Cells Is Brought About by Oxidative-Stress-Mediated Alterations in the Expression of BCL2 Family Members and Is Enhanced on miR-21 Inhibition. J Mol Neurosci. 2015; 57(2):197-202. DOI: 10.1007/s12031-015-0602-x. View

12.

Altman D, Bland J . Standard deviations and standard errors. BMJ. 2005; 331(7521):903. PMC: 1255808. DOI: 10.1136/bmj.331.7521.903. View

13.

Filigheddu N, Sampietro S, Chianale F, Porporato P, Gaggianesi M, Gregnanin I . Diacylglycerol kinase α mediates 17-β-estradiol-induced proliferation, motility, and anchorage-independent growth of Hec-1A endometrial cancer cell line through the G protein-coupled estrogen receptor GPR30. Cell Signal. 2011; 23(12):1988-96. DOI: 10.1016/j.cellsig.2011.07.009. View

14.

Hsu L, Chu N, Lin Y, Kao S . G-Protein Coupled Estrogen Receptor in Breast Cancer. Int J Mol Sci. 2019; 20(2). PMC: 6359026. DOI: 10.3390/ijms20020306. View

15.

Horne E, Diaz P, Cimino P, Jung E, Xu C, Hamel E . A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis. Neurooncol Adv. 2021; 3(1):vdaa165. PMC: 7813200. DOI: 10.1093/noajnl/vdaa165. View

16.

Barton M, Filardo E, Lolait S, Thomas P, Maggiolini M, Prossnitz E . Twenty years of the G protein-coupled estrogen receptor GPER: Historical and personal perspectives. J Steroid Biochem Mol Biol. 2017; 176:4-15. PMC: 5716468. DOI: 10.1016/j.jsbmb.2017.03.021. View

17.

Toran-Allerand C, Tinnikov A, Singh R, Nethrapalli I . 17alpha-estradiol: a brain-active estrogen?. Endocrinology. 2005; 146(9):3843-50. DOI: 10.1210/en.2004-1616. View

18.

Zhao T, Ding Q, Hu J, He S, Shi F, Ma L . GPER expressed on microglia mediates the anti-inflammatory effect of estradiol in ischemic stroke. Brain Behav. 2016; 6(4):e00449. PMC: 4840664. DOI: 10.1002/brb3.449. View

19.

Han N, Heublein S, Jeschke U, Kuhn C, Hester A, Czogalla B . The G-Protein-Coupled Estrogen Receptor (GPER) Regulates Trimethylation of Histone H3 at Lysine 4 and Represses Migration and Proliferation of Ovarian Cancer Cells In Vitro. Cells. 2021; 10(3). PMC: 8001910. DOI: 10.3390/cells10030619. View

20.

Wang X, Yue J, Hu L, Tian Z, Zhang K, Yang L . Activation of G protein-coupled receptor 30 protects neurons by regulating autophagy in astrocytes. Glia. 2019; 68(1):27-43. DOI: 10.1002/glia.23697. View