Journal article
Mechanistic Investigation of the Androgen Receptor DNA-Binding Domain Inhibitor Pyrvinium
ACS omega, Vol.4(2), pp.2472-2481
02/01/2019
DOI: 10.1021/acsomega.8b03205
PMCID: PMC6410682
PMID: 30873507
Abstract
Pyrvinium was identified as the first small molecule inhibitor of the androgen receptor (AR) DNA-binding domain (DBD). It was also among the first small molecules shown to directly inhibit the activity of AR splice variants (ARVs), which has important clinical implications in the treatment of castration-resistant prostate cancer. Important questions about pyrvinium's mechanism of action remain. Here, we demonstrate through mutational analysis that amino acids 609 and 612 are important for pyrvinium action. Nuclear magnetic resonance demonstrates a specific interaction between a soluble pyrvinium derivative and the AR DBD homodimer-DNA complex. Chromatin immunoprecipitation and electrophoretic mobility shift assay experiments demonstrate that, despite an interaction with this complex, pyrvinium does not alter the DNA-binding kinetics in either assay. AR immunoprecipitation followed by mass spectrometry was used to identify proteins whose interaction with AR is altered by pyrvinium. Several splicing factors, including DDX17, had reduced interactions with AR in the presence of pyrvinium. RNA sequencing of prostate cancer cells treated with pyrvinium demonstrated changes in splicing, as well as in several other pathways. However, pyrvinium did not alter the levels of ARVs in several prostate cancer cell lines. Taken together, our new data pinpoint the direct interaction between pyrvinium and AR DBD and shed light on the mechanism by which it inhibits AR transcriptional activity.
Details
- Title: Subtitle
- Mechanistic Investigation of the Androgen Receptor DNA-Binding Domain Inhibitor Pyrvinium
- Creators
- Sumanta K. Pal - City Of Hope National Medical CenterBen Yi Tew - City Of Hope National Medical CenterMinyoung Lim - City Of Hope National Medical CenterBrittany Stankavich - University of IowaMiaoling He - City Of Hope National Medical CenterMiles Pufall - University of IowaWeidong Hu - City Of Hope National Medical CenterYuan Chen - City Of Hope National Medical CenterJeremy O. Jones - City Of Hope National Medical Center
- Resource Type
- Journal article
- Publication Details
- ACS omega, Vol.4(2), pp.2472-2481
- Publisher
- Amer Chemical Soc
- DOI
- 10.1021/acsomega.8b03205
- PMID
- 30873507
- PMCID
- PMC6410682
- ISSN
- 2470-1343
- eISSN
- 2470-1343
- Number of pages
- 10
- Grant note
- Margaret E. Early Research Trust P30CA033572 / National Cancer Institute of the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) P30CA086862 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) World Cancer Research Fund; World Cancer Research Fund International (WCRF)
- Language
- English
- Date published
- 02/01/2019
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984293087902771
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