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GPER1 influences cellular homeostasis and cytostatic drug resistance via influencing long chain ceramide synthesis in breast cancer cells.
- Source :
-
The international journal of biochemistry & cell biology [Int J Biochem Cell Biol] 2019 Jul; Vol. 112, pp. 95-106. Date of Electronic Publication: 2019 May 11. - Publication Year :
- 2019
-
Abstract
- The G protein-coupled estrogen receptor 1 (GPER1) is involved in the regulation of physiological processes such as cellular growth and proliferation, but also in pathophysiological processes such as tumor development. The role of GPER1 in breast cancer is contradictory. Therefore, we investigated the influence of GPER1 overexpression on cellular processes in MCF-7 breast cancer cells. GPER1 overexpression leads to a cell cycle arrest in the G1 phase, induction of autophagy and reduced proliferation. Reduced proliferation was accompanied by a reduced basal respiration and reduced glycolysis rate in GPER1 overexpressing cells. This is presumably ascribable to mitophagy induction following GPER1 overexpression. However, GPER1 overexpressing cells were less sensitive against doxorubicin as compared to control cells. In previous work we showed the effect of transient GPER1 overexpression on the synthesis of several ceramide synthases (CerS) thereby influencing the sphingolipid pathway. Therefore, we investigated CerS expression and sphingolipid level in stable GPER1 overexpressing and control cells. Stable GPER1 overexpression strongly reduced CerS4, CerS5 and CerS6 promoter activity and CerS5 and CerS6 mRNA expression, whereas CerS2 mRNA expression was upregulated. The GPER1 effect on CerS5 promoter is mediated by GSK-3β signaling. In addition, other enzymes of the sphingolipid pathway were upregulated. Our study provides new insights into the role of GPER1 and the activated sphingolipid pathways and how GPER1 may influence cellular processes such as cancer cell survival following chemotherapy. Further studies are needed to investigate the molecular mechanisms leading to these cellular effects. Finding new therapeutic targets for modulating specifically GPER1 in breast tumors may improve endocrine breast cancer therapy.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Subjects :
- Breast Neoplasms genetics
Breast Neoplasms pathology
Ceramides genetics
Female
G1 Phase Cell Cycle Checkpoints
Humans
MCF-7 Cells
Neoplasm Proteins genetics
Oxidoreductases genetics
Receptors, Estrogen genetics
Receptors, G-Protein-Coupled genetics
Breast Neoplasms metabolism
Ceramides biosynthesis
Cytostatic Agents pharmacology
Drug Resistance, Neoplasm drug effects
Homeostasis drug effects
Neoplasm Proteins metabolism
Oxidoreductases metabolism
Receptors, Estrogen metabolism
Receptors, G-Protein-Coupled metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-5875
- Volume :
- 112
- Database :
- MEDLINE
- Journal :
- The international journal of biochemistry & cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 31082617
- Full Text :
- https://doi.org/10.1016/j.biocel.2019.05.002