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Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice. Mol Oncol 2024 Aug;18(8):1966-1979

Date

04/12/2024

Pubmed ID

38605607

Pubmed Central ID

PMC11306517

DOI

10.1002/1878-0261.13637

Scopus ID

2-s2.0-85190504464 (requires institutional sign-in at Scopus site)

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.

Author List

Karan D, Dubey S, Gunewardena S, Iczkowski KA, Singh M, Liu P, Poletti A, Choo YM, Chen HZ, Hamann MT

Author

Hui-Zi Chen MD, PhD Assistant Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Line, Tumor
Cell Proliferation
DNA
Gene Expression Regulation, Neoplastic
Humans
Male
Mice
Mice, Nude
Prostatic Neoplasms
Receptors, Androgen
Transcription, Genetic
Xenograft Model Antitumor Assays