Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor

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 tha...

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Bibliographic Details
Published in:PloS one 2013-10, Vol.8 (10), p.e78479
Main Authors: Mahmoud, Abeer M, Zhu, Tian, Parray, Aijaz, Siddique, Hifzur R, Yang, Wancai, Saleem, Mohammad, Bosland, Maarten C
Format: Article
Language:English
Subjects:
Activation
Amino Acid Substitution
Androgen receptors
Androgens
Androgens - chemistry
Androgens - pharmacology
Angiogenesis inhibitors
Anticarcinogenic Agents - chemistry
Anticarcinogenic Agents - pharmacology
Apoptosis
Cancer
Cell Line, Tumor
Cell Nucleus - genetics
Cell Nucleus - metabolism
Cell Nucleus - pathology
Cell proliferation
Cell Proliferation - drug effects
Chemical compounds
Gene Expression Regulation, Neoplastic - drug effects
Genetic aspects
Genistein
Genistein - chemistry
Genistein - pharmacology
Glycine max - chemistry
Health aspects
Humans
Isoflavones
Kinases
Localization
Male
Mutants
Mutation
Mutation, Missense
Neoplasm Proteins - agonists
Neoplasm Proteins - biosynthesis
Neoplasm Proteins - chemistry
Physiological aspects
Physiological effects
Physiology
Phytosterols - chemistry
Phytosterols - pharmacology
Prostate cancer
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Receptors, Androgen - biosynthesis
Receptors, Androgen - genetics
Soy products
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0078479