Differential Effects of Genistein on Prostate Cancer Cells Depend on Mutational Status of the Androgen Receptor

Abeer M. Mahmoud, Tian Zhu, Aijaz Parray, Hifzur R. Siddique, Wancai Yang, Mohammad Saleem Bhat, Maarten C. Bosland

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Blocking the androgen receptor (AR) activity is the main goal of therapies for advanced prostate cancer (PCa). However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent) activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A) mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 μmol/L) stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.

Original languageEnglish (US)
Article numbere78479
JournalPloS one
Volume8
Issue number10
DOIs
StatePublished - Oct 22 2013

Fingerprint

Dive into the research topics of 'Differential Effects of Genistein on Prostate Cancer Cells Depend on Mutational Status of the Androgen Receptor'. Together they form a unique fingerprint.

Cite this