scholarly journals Characterization of a Steroid Receptor Coactivator Small Molecule Stimulator that Overstimulates Cancer Cells and Leads to Cell Stress and Death

Cancer Cell ◽  
2015 ◽  
Vol 28 (2) ◽  
pp. 240-252 ◽  
Author(s):  
Lei Wang ◽  
Yang Yu ◽  
Dar-Chone Chow ◽  
Fei Yan ◽  
Chih-Chao Hsu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Small Molecule ◽  
Steroid Receptor ◽  
Cell Stress ◽  
Steroid Receptor Coactivator

scholarly journals Steroid Receptor Coactivator-2 Controls the Pentose Phosphate Pathway through RPIA in Human Endometrial Cancer Cells

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Maria M. Szwarc ◽  
Ramakrishna Kommagani ◽  
Vasanta Putluri ◽  
Julien Dubrulle ◽  
Fabio Stossi ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Cells ◽  
Pentose Phosphate Pathway ◽  
Steroid Receptor ◽  
Pentose Phosphate ◽  
Steroid Receptor Coactivator

scholarly journals Identification of Verrucarin A as a Potent and Selective Steroid Receptor Coactivator-3 Small Molecule Inhibitor

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e95243 ◽  
Author(s):  
Fei Yan ◽  
Yang Yu ◽  
Dar-Chone Chow ◽  
Timothy Palzkill ◽  
Franck Madoux ◽  
...  
Keyword(s):  
Small Molecule ◽  
Steroid Receptor ◽  
Small Molecule Inhibitor ◽  
Steroid Receptor Coactivator ◽  
Molecule Inhibitor

scholarly journals Tyrosine Phosphorylation of the Nuclear Receptor Coactivator AIB1/SRC-3 Is Enhanced by Abl Kinase and Is Required for Its Activity in Cancer Cells

2008 ◽  
Vol 28 (21) ◽  
pp. 6580-6593 ◽  
Author(s):  
Annabell S. Oh ◽  
John T. Lahusen ◽  
Christopher D. Chien ◽  
Mark P. Fereshteh ◽  
Xiaolong Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cancer Cells ◽  
Tyrosine Phosphorylation ◽  
Critical Role ◽  
Steroid Receptor ◽  
Viral Oncogene ◽  
Steroid Receptor Coactivator ◽  
Abl Kinase ◽  
Viral Oncogene Homolog

ABSTRACT Overexpression and activation of the steroid receptor coactivator amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) have been shown to have a critical role in oncogenesis and are required for both steroid and growth factor signaling in epithelial tumors. Here, we report a new mechanism for activation of SRC coactivators. We demonstrate regulated tyrosine phosphorylation of AIB1/SRC-3 at a C-terminal tyrosine residue (Y1357) that is phosphorylated after insulin-like growth factor 1, epidermal growth factor, or estrogen treatment of breast cancer cells. Phosphorylated Y1357 is increased in HER2/neu (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2) mammary tumor epithelia and is required to modulate AIB1/SRC-3 coactivation of estrogen receptor alpha (ERα), progesterone receptor B, NF-κB, and AP-1-dependent promoters. c-Abl (v-Abl Abelson murine leukemia viral oncogene homolog 1) tyrosine kinase directly phosphorylates AIB1/SRC-3 at Y1357 and modulates the association of AIB1 with c-Abl, ERα, the transcriptional cofactor p300, and the methyltransferase coactivator-associated arginine methyltransferase 1, CARM1. AIB1/SRC-3-dependent transcription and phenotypic changes, such as cell growth and focus formation, can be reversed by an Abl kinase inhibitor, imatinib. Thus, the phosphorylation state of Y1357 can function as a molecular on/off switch and facilitates the cross talk between hormone, growth factor, and intracellular kinase signaling pathways in cancer.

scholarly journals AIB1 sequestration by androgen receptor inhibits estrogen-dependent cyclin D1 expression in breast cancer cells

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Francesca De Amicis ◽  
Chiara Chiodo ◽  
Catia Morelli ◽  
Ivan Casaburi ◽  
Stefania Marsico ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Breast Tumor ◽  
Breast Cancer Cells ◽  
Promoter Activity ◽  
Gene Promoter ◽  
Steroid Receptor ◽  
Steroid Receptor Coactivator

Abstract Background Androgens, through their own receptor, play a protective role on breast tumor development and progression and counterbalance estrogen-dependent growth stimuli which are intimately linked to breast carcinogenesis. Methods Cell counting by trypan blu exclusion was used to study androgen effect on estrogen-dependent breast tumor growth. Quantitative Real Time RT–PCR, western blotting, transient transfection, protein immunoprecipitation and chromatin immunoprecipitation assays were carried out to investigate how androgen treatment and/or androgen receptor overexpression influences the functional interaction between the steroid receptor coactivator AIB1 and the estrogen- or androgen receptor which, in turn affects the estrogen-induced cyclin D1 gene expression in MCF-7 breast cancer cells. Data were analyzed by ANOVA. Results Here we demonstrated, in estrogen receptor α (ERα)-positive breast cancer cells, an androgen-dependent mechanism through which ligand-activated androgen receptor (AR) decreases estradiol-induced cyclin D1 protein, mRNA and gene promoter activity. These effects involve the competition between AR and ERα for the interaction with the steroid receptor coactivator AIB1, a limiting factor in the functional coupling of the ERα with the cyclin D1 promoter. Indeed, AIB1 overexpression is able to reverse the down-regulatory effects exerted by AR on ERα-mediated induction of cyclin D1 promoter activity. Co-immunoprecipitation studies indicated that the preferential interaction of AIB1 with ERα or AR depends on the intracellular expression levels of the two steroid receptors. In addition, ChIP analysis evidenced that androgen administration decreased E2-induced recruitment of AIB1 on the AP-1 site containing region of the cyclin D1 gene promoter. Conclusions Taken together all these data support the hypothesis that AIB1 sequestration by AR may be an effective mechanism to explain the reduction of estrogen-induced cyclin D1 gene activity. In estrogen-dependent breast cancer cell proliferation, these findings reinforce the possibility that targeting AR signalling may potentiate the effectiveness of anti-estrogen adjuvant therapies.

scholarly journals Development of potent small-molecule inhibitors to drug the undruggable steroid receptor coactivator-3

2016 ◽  
Vol 113 (18) ◽  
pp. 4970-4975 ◽  
Author(s):  
Xianzhou Song ◽  
Jianwei Chen ◽  
Mingkun Zhao ◽  
Chengwei Zhang ◽  
Yang Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Small Molecule ◽  
Protein Interactions ◽  
High Throughput Screening ◽  
Small Molecule Inhibitors ◽  
Structural Information ◽  
Steroid Receptor ◽  
Functional Assay ◽  
Lipinski’S Rule ◽  
Steroid Receptor Coactivator

Protein–protein interactions (PPIs) play a central role in most biological processes, and therefore represent an important class of targets for therapeutic development. However, disrupting PPIs using small-molecule inhibitors (SMIs) is challenging and often deemed as “undruggable.” We developed a cell-based functional assay for high-throughput screening to identify SMIs for steroid receptor coactivator-3 (SRC-3 or AIB1), a large and mostly unstructured nuclear protein. Without any SRC-3 structural information, we identified SI-2 as a highly promising SMI for SRC-3. SI-2 meets all of the criteria of Lipinski’s rule [Lipinski et al. (2001) Adv Drug Deliv Rev 46(1-3):3–26] for a drug-like molecule and has a half-life of 1 h in a pharmacokinetics study and a reasonable oral availability in mice. As a SRC-3 SMI, SI-2 can selectively reduce the transcriptional activities and the protein concentrations of SRC-3 in cells through direct physical interactions with SRC-3, and selectively induce breast cancer cell death with IC50 values in the low nanomolar range (3–20 nM), but not affect normal cell viability. Furthermore, SI-2 can significantly inhibit primary tumor growth and reduce SRC-3 protein levels in a breast cancer mouse model. In a toxicology study, SI-2 caused minimal acute cardiotoxicity based on a hERG channel blocking assay and an unappreciable chronic toxicity to major organs based on histological analyses. We believe that this work could significantly improve breast cancer treatment through the development of “first-in-class” drugs that target oncogenic coactivators.

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