GPER1 influences cellular homeostasis and cytostatic drug resistance via influencing long chain ceramide synthesis in breast cancer cells.
GPER1 influences cellular homeostasis and cytostatic drug resistance via influencing long chain ceramide synthesis in breast cancer cells.
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DOI：
10.1016/j.biocel.2019.05.002
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发表时间：
2019-07
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通讯作者：
Marthe-Susanna Wegner;L. Gruber;Nina Schömel;S. Trautmann;Sebastian Brachtendorf;D. Fuhrmann;Y. Schreiber;Catherine Olesch;B. Brüne;G. Geisslinger;S. Grösch
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作者：
Marthe-Susanna Wegner;L. Gruber;Nina Schömel;S. Trautmann;Sebastian Brachtendorf;D. Fuhrmann;Y. Schreiber;Catherine Olesch;B. Brüne;G. Geisslinger;S. Grösch
G 蛋白偶联雌激素受体 1 (GPER1) 参与细胞生长和增殖等生理过程的调节，也参与肿瘤发展等病理生理过程。 GPER1 在乳腺癌中的作用是矛盾的。因此，我们研究了 GPER1 过表达对 MCF-7 乳腺癌细胞细胞过程的影响。 GPER1 过度表达导致细胞周期停滞在 G1 期，诱导自噬并减少增殖。 GPER1 过表达细胞中增殖减少伴随着基础呼吸减少和糖酵解率降低。这可能归因于 GPER1 过度表达后线粒体自噬的诱导。然而，与对照细胞相比，GPER1 过表达细胞对阿霉素的敏感性较低。在之前的工作中，我们展示了瞬时 GPER1 过表达对几种神经酰胺合酶 (CerS) 合成的影响，从而影响鞘脂途径。因此，我们研究了稳定 GPER1 过表达和对照细胞中的 CerS 表达和鞘脂水平。稳定的 GPER1 过表达强烈降低 CerS4、CerS5 和 CerS6 启动子活性以及 CerS5 和 CerS6 mRNA 表达，而 CerS2 mRNA 表达上调。 GPER1 对 CerS5 启动子的作用是由 GSK-3β 信号传导介导的。此外，鞘脂途径的其他酶也上调。我们的研究为 GPER1 和激活的鞘脂通路的作用以及 GPER1 如何影响化疗后癌细胞存活等细胞过程提供了新的见解。需要进一步的研究来调查导致这些细胞效应的分子机制。寻找新的治疗靶点来特异性调节乳腺肿瘤中的 GPER1 可能会改善内分泌乳腺癌的治疗。
TheG 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 severalceramide 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.