Karan, Dev and Dubey, Seema and Gunewardena, Sumedha and Iczkowski, Kenneth A. and Singh, Manohar and Liu, Pengyuan and Poletti, Angelo and Choo, Yeun-Mun and Chen, Hui-Zi and Hamann, Mark T. (2024) Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice. Molecular Oncology, 18 (8). pp. 1966-1979. ISSN 1574-7891, DOI https://doi.org/10.1002/1878-0261.13637.
Full text not available from this repository.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.
| Item Type: | Article |
|---|---|
| Funders: | Medicines for Malaria Venture (NCCIH RO1AT007318) |
| Uncontrolled Keywords: | androgen receptor; manzamine A; prostate cancer |
| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
| Divisions: | Faculty of Science > Department of Chemistry |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 09 Jan 2025 02:16 |
| Last Modified: | 09 Jan 2025 02:16 |
| URI: | http://eprints.um.edu.my/id/eprint/46994 |
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