| Autor: |
Diep-Khanh Ho Vo, Roland Hartig, Sönke Weinert, Johannes Haybaeck, Norbert Nass |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
Biomolecules, Vol 9, Iss 9, p 503 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
2218-273X |
| DOI: |
10.3390/biom9090503 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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