ECE2006 Oral Communications Steroids and reproductive endocrinology (8 abstracts)
Role of the Hu proteins, HuR and HuD, and αCP1 in the regulation of androgen receptor expression and activity in prostate cancer cells
CF Down 1 , RR Lareu 1 , B Granath 1 , DJ Beveridge 1 , H Furneaux 2 , J Bentel 3 & PJ Leedman 1
1Laboratory for Cancer Medicine, Centre for Medical Research, Western Australian Institute for Medical Research, and School of Medicine and Pharmacology, the University of Western Australia, Perth, Western Australia, Australia; 2Vascular Biology Programme, Department of Physiology, University of Connecticut Health Centre, Farmington, Connecticut, United States; 3School of Surgery and Pathology and Department of Pathology, Royal Perth Hospital, the University of Western Australia, Perth, Western Australia, Australia.
The primary treatment for prostate cancer (PCa) involves androgen ablation, halting tumour growth through down-regulation of androgen-regulated proliferative genes1. Frequently PCa progresses to an androgen-independent state and untreatable disease. The Androgen receptor (AR) continues to be expressed in many of these tumours, often associated with androgen-independent activation of the AR signalling pathway. Thus, the aim of the study is to understand regulation of AR expression in these cells. MRNA decay plays a critical role in AR regulation in PCa cells2. We have identified a specific, UC-rich region in the 3′ untranslated region (UTR) of the AR mRNA that binds, in vitro and in vivo, RNA-binding proteins (HuR, HuD and αCP1), known to modulate mRNA turnover in other systems3,4,5. Mutations in this region abrogate binding of these proteins, and decrease luciferase reporter activity when inserted 3′ of the luciferase gene. Significantly, HuD, usually restricted to neurons, is expressed in a range of primary PCa samples. We aimed to determine the role of HuR/D and αCP1 in the regulation of AR expression and activity in PCa cells. We found that AR protein levels were significantly decreased in cells with levels of HuR reduced by RNAi treatment, and preliminary results indicate that knockdown of HuR reduces half-life of AR mRNA. In addition, alteration of HuR or HuD in LNCaP cells moderated cell proliferation. Taken together, these data implicate the Hu proteins, HuR and HuD, as novel AR mRNA-binding proteins that play an important role as regulators of AR expression and signalling in PCa cells. As such, they may represent potential therapeutic targets.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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