Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Vo, DH; Hartig, R; Weinert, S; Haybaeck, J; Nass, N.
G-Protein-Coupled Estrogen Receptor (GPER)-Specific Agonist G1 Induces ER Stress Leading to Cell Death in MCF-7 Cells.
Biomolecules. 2019; 9(9):
Doi: 10.3390/biom9090503
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- Co-Autor*innen der Med Uni Graz
- Haybäck Johannes
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- Abstract:
- 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 (Ca2+). The purpose of this study is to elucidate the mechanism of G1-induced cell death by focusing on the connection between G1-induced Ca2+ depletion and endoplasmic reticulum (ER) stress in the estrogen receptor positive breast cancer cell line MCF-7. We found that G1-induced ER Ca2+ 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 Ca2+ is responsible for G1-induced cell death via the pro-death UPR signaling.
- Find related publications in this database (using NLM MeSH Indexing)
- Activating Transcription Factor 6 - metabolism
- Breast Neoplasms - drug therapy
- Breast Neoplasms - metabolism
- Calcium - metabolism
- Cell Proliferation - drug effects
- Cell Survival - drug effects
- Cyclopentanes - pharmacology
- Endoplasmic Reticulum Stress - drug effects
- Endoribonucleases - metabolism
- Female -
- Humans -
- MCF-7 Cells -
- Phosphorylation - drug effects
- Protein-Serine-Threonine Kinases - metabolism
- Quinolines - pharmacology
- Receptors, Estrogen -
- Receptors, G-Protein-Coupled - agonists
- Unfolded Protein Response - drug effects
- eIF-2 Kinase - metabolism
- Find related publications in this database (Keywords)
- GPER
- GPER-specific agonist G1
- UPR signaling
- Ca2+ efflux
- ER stress
- JNK
- CAMKII
- breast cancer