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© 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

The androgen receptor (AR) is the main driver in the development of castration‐resistant prostate cancer, where the emergence of AR splice variants leads to treatment‐resistant disease. Through detailed molecular studies of the marine alkaloid manzamine A (MA), we identified transcription factor E2F8 as a previously unknown regulator of AR transcription that prevents AR synthesis in prostate cancer cells. MA significantly inhibited the growth of various prostate cancer cell lines and was highly effective in inhibiting xenograft tumor growth in mice without any pathophysiological perturbations in major organs. MA suppressed the full‐length AR (AR‐FL), its spliced variant AR‐V7, and the AR‐regulated prostate‐specific antigen (PSA; also known as KLK3) and human kallikrein 2 (hK2; also known as KLK2) genes. RNA sequencing (RNA‐seq) analysis and protein modeling studies revealed E2F8 interactions with DNA as a potential novel target of MA, suppressing AR transcription and its synthesis. This novel mechanism of blocking AR biogenesis via E2F8 may provide an opportunity to control therapy‐resistant prostate cancer over the currently used AR antagonists designed to target different parts of the AR gene.

Details

Title
Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8‐DNA interactions and effectively inhibits prostate tumor growth in mice
Author
Karan, Dev 1   VIAFID ORCID Logo  ; Dubey, Seema 1 ; Gunewardena, Sumedha 2 ; Iczkowski, Kenneth A. 1 ; Singh, Manohar 1 ; Liu, Pengyuan 3 ; Poletti, Angelo 4 ; Choo, Yeun‐Mun 5 ; Chen, Hui‐Zi 6 ; Hamann, Mark T. 7 

 Department of Pathology, and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA 
 Department of Cell Biology and Physiology, University of Kansas Medical Center, KS, USA 
 Department of Physiology and Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI, USA 
 Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy 
 Department of Chemistry, University of Malaya, Kuala Lumpur, Malaysia 
 Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA 
 Department of Drug Discovery and Biomedical Sciences and Public Health, Colleges of Pharmacy and Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA 
Pages
1966-1979
Section
Research Article
Publication year
2024
Publication date
Aug 1, 2024
Publisher
John Wiley & Sons, Inc.
ISSN
15747891
e-ISSN
18780261
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3090096764
Copyright
© 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.