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TBECH, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane, alters androgen receptor regulation in response to mutations associated with prostate cancer
Örebro University, School of Science and Technology. (Biology, Örebro Life Science Center)
Örebro University, School of Science and Technology. (Biology, Örebro Life Science Center)
Örebro University, School of Science and Technology. (Biology, Örebro Life Science Center)ORCID iD: 0000-0003-3302-7106
Örebro University, School of Science and Technology. (Biology, Örebro Life Science Center)ORCID iD: 0000-0001-7336-6335
2016 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 307, p. 91-101Article in journal (Refereed) Published
Abstract [en]

Point mutations in the AR ligand-binding domain (LBD) can result in altered AR structures leading to changes of ligand specificity and functions. AR mutations associated to prostate cancer (PCa) have been shown to result in receptor activation by non-androgenic substances and anti-androgenic drugs. Two AR mutations known to alter the function of anti-androgens are the ART877A mutation, which is frequently detected mutation in PCa tumors and the ARW741C that is rare and has been derived in vitro following exposure of cells to the anti-androgen bicalutamide. AR activation by non-androgenic environmental substances has been suggested to affect PCa progression. In the present study we investigated the effect of AR mutations (ARW741C and ART877A) on the transcriptional activation following exposure of cells to an androgenic brominated flame retardant, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH, also named DBE-DBCH). The AR mutations resulted in higher interaction energies and increased transcriptional activation in response to TBECH diastereomer exposures. The ART877A mutation rendered AR highly responsive to low levels of DHT and TBECH and led to increased AR nuclear translocation. Gene expression analysis showed a stronger induction of AR target genes in LNCaP cells (ART877A) compared to T-47D cells (ARWT) following TBECH exposure. Furthermore, AR knockdown experiments confirmed the AR dependency of these responses. The higher sensitivity of ART877A and ARW741C to low levels of TBECH suggests that cells with these AR mutations are more susceptible to androgenic endocrine disrupters.

Place, publisher, year, edition, pages
Elsevier, 2016. Vol. 307, p. 91-101
Keywords [en]
Steroid hormone, endocrine disrupting compounds, nuclear localization, receptor, nuclear localization
National Category
Cell Biology Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:oru:diva-51471DOI: 10.1016/j.taap.2016.07.018ISI: 000382417400009PubMedID: 27473015Scopus ID: 2-s2.0-84980328031OAI: oai:DiVA.org:oru-51471DiVA, id: diva2:951110
Funder
Knowledge Foundation
Note

Funding Agency:

Örebro University, Sweden 

Available from: 2016-08-05 Created: 2016-08-02 Last updated: 2018-01-10Bibliographically approved

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Kharlyngdoh, Joubert BanjopAsnake, SolomonPradhan, AjayOlsson, Per-Erik

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