G-Protein-Coupled Estrogen Receptor (GPER)-Specific Agonist G1 Induces ER Stress Leading to Cell Death in MCF-7 Cells
The G-protein-coupled estrogen receptor (GPER) mediates rapid non-genomic effects of estrogen. Although GPER is able to induce proliferation, it is down-regulated in breast, ovarian and colorectal cancer. During cancer progression, high expression levels of GPER are favorable for patients’...
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doaj-3812991b3508476eba92fb00bf0c2e5d2020-11-25T01:33:56ZengMDPI AGBiomolecules2218-273X2019-09-019950310.3390/biom9090503biom9090503G-Protein-Coupled Estrogen Receptor (GPER)-Specific Agonist G1 Induces ER Stress Leading to Cell Death in MCF-7 CellsDiep-Khanh Ho Vo0Roland Hartig1Sönke Weinert2Johannes Haybaeck3Norbert Nass4Department of Pathology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, GermanyInstitute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, GermanyDepartment of Cardiology, Medical Faculty, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, GermanyDepartment of Pathology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, GermanyDepartment of Pathology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, GermanyThe G-protein-coupled estrogen receptor (GPER) mediates rapid non-genomic effects of estrogen. Although GPER is able to induce proliferation, it is down-regulated in breast, ovarian and colorectal cancer. During cancer progression, high expression levels of GPER are favorable for patients’ survival. The GPER-specific agonist G1 leads to an inhibition of cell proliferation and an elevated level of intracellular calcium (Ca<sup>2+</sup>). The purpose of this study is to elucidate the mechanism of G1-induced cell death by focusing on the connection between G1-induced Ca<sup>2+</sup> depletion and endoplasmic reticulum (ER) stress in the estrogen receptor positive breast cancer cell line MCF-7. We found that G1-induced ER Ca<sup>2+</sup> efflux led to the activation of the unfolded protein response (UPR), indicated by the phosphorylation of IRE1α and PERK and the cleavage of ATF6. The pro-survival UPR signaling was activated via up-regulation of the ER chaperon protein GRP78 and translational attenuation indicated by eIF2-α phosphorylation. However, the accompanying pro-death UPR signaling is profoundly activated and responsible for ER stress-induced cell death. Mechanistically, PERK-phosphorylation-induced JNK-phosphorylation and IRE1α-phosphorylation, which further triggered CAMKII-phosphorylation, are both implicated in G1-induced cell death. Our study indicates that loss of ER Ca<sup>2+</sup> is responsible for G1-induced cell death via the pro-death UPR signaling.https://www.mdpi.com/2218-273X/9/9/503GPERGPER-specific agonist G1UPR signalingCa<sup>2+</sup> effluxER stressJNKCAMKIIbreast cancer |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Diep-Khanh Ho Vo Roland Hartig Sönke Weinert Johannes Haybaeck Norbert Nass |
spellingShingle |
Diep-Khanh Ho Vo Roland Hartig Sönke Weinert Johannes Haybaeck Norbert Nass G-Protein-Coupled Estrogen Receptor (GPER)-Specific Agonist G1 Induces ER Stress Leading to Cell Death in MCF-7 Cells Biomolecules GPER GPER-specific agonist G1 UPR signaling Ca<sup>2+</sup> efflux ER stress JNK CAMKII breast cancer |
author_facet |
Diep-Khanh Ho Vo Roland Hartig Sönke Weinert Johannes Haybaeck Norbert Nass |
author_sort |
Diep-Khanh Ho Vo |
title |
G-Protein-Coupled Estrogen Receptor (GPER)-Specific Agonist G1 Induces ER Stress Leading to Cell Death in MCF-7 Cells |
title_short |
G-Protein-Coupled Estrogen Receptor (GPER)-Specific Agonist G1 Induces ER Stress Leading to Cell Death in MCF-7 Cells |
title_full |
G-Protein-Coupled Estrogen Receptor (GPER)-Specific Agonist G1 Induces ER Stress Leading to Cell Death in MCF-7 Cells |
title_fullStr |
G-Protein-Coupled Estrogen Receptor (GPER)-Specific Agonist G1 Induces ER Stress Leading to Cell Death in MCF-7 Cells |
title_full_unstemmed |
G-Protein-Coupled Estrogen Receptor (GPER)-Specific Agonist G1 Induces ER Stress Leading to Cell Death in MCF-7 Cells |
title_sort |
g-protein-coupled estrogen receptor (gper)-specific agonist g1 induces er stress leading to cell death in mcf-7 cells |
publisher |
MDPI AG |
series |
Biomolecules |
issn |
2218-273X |
publishDate |
2019-09-01 |
description |
The G-protein-coupled estrogen receptor (GPER) mediates rapid non-genomic effects of estrogen. Although GPER is able to induce proliferation, it is down-regulated in breast, ovarian and colorectal cancer. During cancer progression, high expression levels of GPER are favorable for patients’ survival. The GPER-specific agonist G1 leads to an inhibition of cell proliferation and an elevated level of intracellular calcium (Ca<sup>2+</sup>). The purpose of this study is to elucidate the mechanism of G1-induced cell death by focusing on the connection between G1-induced Ca<sup>2+</sup> depletion and endoplasmic reticulum (ER) stress in the estrogen receptor positive breast cancer cell line MCF-7. We found that G1-induced ER Ca<sup>2+</sup> efflux led to the activation of the unfolded protein response (UPR), indicated by the phosphorylation of IRE1α and PERK and the cleavage of ATF6. The pro-survival UPR signaling was activated via up-regulation of the ER chaperon protein GRP78 and translational attenuation indicated by eIF2-α phosphorylation. However, the accompanying pro-death UPR signaling is profoundly activated and responsible for ER stress-induced cell death. Mechanistically, PERK-phosphorylation-induced JNK-phosphorylation and IRE1α-phosphorylation, which further triggered CAMKII-phosphorylation, are both implicated in G1-induced cell death. Our study indicates that loss of ER Ca<sup>2+</sup> is responsible for G1-induced cell death via the pro-death UPR signaling. |
topic |
GPER GPER-specific agonist G1 UPR signaling Ca<sup>2+</sup> efflux ER stress JNK CAMKII breast cancer |
url |
https://www.mdpi.com/2218-273X/9/9/503 |
work_keys_str_mv |
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