The xenoestrogen bisphenol A induces inappropriate androgen receptor activation and mitogenesis in prostatic adenocarcinoma cells.
Treatment for prostatic adenocarcinoma is reliant on the initial androgen dependence of this tumor type. The goal of therapy is to eliminate androgen receptor activity, either through direct inhibition of the receptor or through inhibition of androgen synthesis. Although this course of therapy is initially effective, androgen-refractory tumors ultimately arise and lead to patient morbidity. Factors contributing to the transition from a state of androgen dependence to the androgen-refractory state are poorly understood, but clinical evidence in androgen-refractory tumors suggests that the androgen receptor is inappropriately activated in these cells. Thus, the mechanisms that contribute to inappropriate (androgen-independent) activation of the androgen receptor (AR) is an area of intensive research. Here we demonstrate that bisphenol A (BPA), a polycarbonate plastic monomer and established xenoestrogen, initiates androgen-independent proliferation in human prostatic adenocarcinoma (LNCaP) cells. The mitogenic capacity of BPA occurred in the nanomolar range, indicating that little BPA is required to stimulate proliferation. We show that BPA stimulated nuclear translocation of the tumor-derived receptor (AR-T877A), albeit with delayed kinetics compared with dihydrotestosterone. This translocation event was followed by specific DNA binding at androgen response elements, as shown by electrophoretic mobility shift assays. Moreover, the ability of BPA to stimulate AR-T877A activity was demonstrated by reporter assays and by analysis of an endogenous AR target gene, prostate-specific antigen. Thus, BPA is able to activate AR-T877A in the absence of androgens. Lastly, full mitogenic function of BPA is dependent on activation of the tumor-derived AR-T877A. These data implicate BPA as an inappropriate mitogen for prostatic adenocarcinoma cells and provide the impetus to study the consequence of BPA exposure on prostate cancer.
Wetherill
Yelena B
YB
Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521, USA.
Petre
Christin E
CE
Monk
Kelly R
KR
Puga
Alvaro
A
Knudsen
Karen E
KE
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D001559:Benzhydryl Compounds; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005434:Flow Cytometry; D017930:Genes, Reporter; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D008297:Male; D010636:Phenols / Q000494:pharmacology*; D010957:Plasmids / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D001973:Bromodeoxyuridine; D013196:Dihydrotestosterone; D004968:Estrogens, Non-Steroidal; D010636:Phenols; D011944:Receptors, Androgen; C006780:bisphenol A; D000098826:Bisphenol A Compounds