Affiliations 

  • 1 Department of Pathology, and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
  • 2 Department of Cell Biology and Physiology, University of Kansas Medical Center, KS, USA
  • 3 Department of Physiology and Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
  • 4 Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy
  • 5 Department of Chemistry, University of Malaya, Kuala Lumpur, Malaysia
  • 6 Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
  • 7 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
Mol Oncol, 2024 Apr 11.
PMID: 38605607 DOI: 10.1002/1878-0261.13637

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.