Identification of estrogen receptor ligands leading to activation of non-genomic signaling pathways while exhibiting only weak transcriptional activity
The Journal of steroid biochemistry and molecular biology, 2006•Elsevier
Estrogen receptors (ERs) stimulate genomic effects by acting as nuclear transcription factors
as well as non-genomic effects by activating distinct cytoplasmic protein kinase cascades.
Non-genomic effects have been implicated in numerous cellular processes, such as
proliferation, differentiation, apoptosis and vasorelaxation. To exploit non-genomic effects
mediated by ERα for novel hormone replacement regimens, we screened a focused library
of steroid receptor ligands to identify compounds exhibiting properties different from …
as well as non-genomic effects by activating distinct cytoplasmic protein kinase cascades.
Non-genomic effects have been implicated in numerous cellular processes, such as
proliferation, differentiation, apoptosis and vasorelaxation. To exploit non-genomic effects
mediated by ERα for novel hormone replacement regimens, we screened a focused library
of steroid receptor ligands to identify compounds exhibiting properties different from …
Estrogen receptors (ERs) stimulate genomic effects by acting as nuclear transcription factors as well as non-genomic effects by activating distinct cytoplasmic protein kinase cascades. Non-genomic effects have been implicated in numerous cellular processes, such as proliferation, differentiation, apoptosis and vasorelaxation. To exploit non-genomic effects mediated by ERα for novel hormone replacement regimens, we screened a focused library of steroid receptor ligands to identify compounds exhibiting properties different from estradiol, i.e. substances that selectively stimulate non-genomic signal transduction pathways while exhibiting low genomic activities. Treatment of breast cancer cells and osteosarcoma cells with estradiol, estren, substance A and substance B led to non-genomic activation of Akt (protein kinase B) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling cascades mediated by Src (Rous Sarcoma Virus, non-receptor tyrosine kinase) and phosphatidylinositol-3-kinase (PI3K) stimulation. Such compounds leading to prominent Akt/ERK activation but exhibiting only weak genomic properties were applied in vasorelaxation assays, modeling physiological non-genomic ER responses. As expected from PI3K and Src activation data, substances were as effective as estradiol in mediating vasorelaxation. We assume that these pathway-selective estrogen receptor ligands may serve as potent lead structures for novel hormone replacement strategies exhibiting lesser side effects than the existing treatment paradigms.
Elsevier