Abstract
Dihydrotestosterone (DHT) is regarded as the most potent natural androgen and is implicated in the development and progression of castration resistant prostate cancer (CRPC). Under castrate conditions, DHT is produced from the metabolism of the adrenal androgen precursors, DHEA and androstenedione. Recent studies have shown that the adrenal steroid 11β-hydroxyandrostenedione (11OHA4) serves as the precursor to the androgens 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT). In this study we comprehensively assess the androgenic activity of 11KT and 11KDHT. This is the first study, to our knowledge, to show that 11KT and 11KDHT, like T and DHT, are potent and efficacious agonists of the human androgen receptor (AR) and induced both the expression of representative AR-regulated genes as well as cellular proliferation in the androgen dependent prostate cancer cell lines, LNCaP and VCaP. Proteomic analysis revealed that 11KDHT regulated the expression of more AR-regulated proteins than DHT in VCaP cells, while in vitro conversion assays showed that 11KT and 11KDHT are metabolized at a significantly lower rate in both LNCaP and VCaP cells when compared to T and DHT, respectively. Our findings show that 11KT and 11KDHT are bona fide androgens capable of inducing androgen-dependant gene expression and cell growth, and that these steroids have the potential to remain active longer than T and DHT due to the decreased rate at which they are metabolised. Collectively, our data demonstrates that 11KT and 11KDHT likely play a vital, but overlooked, role in the development and progression of CRPC.
Highlights
Prostate cancer (PCa) is the second most common cancer among men worldwide [1] with androgen deprivation therapy (ADT) being the first line treatment for advanced PCa since androgen signalling is essential for normal and malignant growth of prostate tissue
Using COS-1 cells transiently transfected with a human androgen receptor (AR) expression vector and a selective-AR androgen response element (ARE) driven luciferase reporter construct, we show that 11KT and 11KDHT display similar maximal induction (p > 0.05) as Mib and DHT, confirming that they are both full AR agonists (Fig 2)
In order to elucidate the potential mechanism by which 11KDHT and 11KT induce greater fold change in endogenous AR-regulated gene expression than DHT and T, respectively, we investigated the rate at which these steroids are metabolised by LNCaP and VCaP cells
Summary
Prostate cancer (PCa) is the second most common cancer among men worldwide [1] with androgen deprivation therapy (ADT) being the first line treatment for advanced PCa since androgen signalling is essential for normal and malignant growth of prostate tissue. Most men experience only short term regression (2–3 years), with most patients developing the more aggressive castration-resistant PCa (CRPC) which is associated with poor survival rates [2]. The majority of evidence suggests that CRPC develops as a result of the reactivation of androgen receptor (AR) signalling despite castrate levels of T ( 50 ng/dL) [3,4,5]. The AR and AR-regulated genes are expressed in most clinical cases of CRPC demonstrating that the AR axis is reactivated and drives tumour growth [4,5]. Mechanisms proposed to be responsible for the continued AR activation include up-regulation of AR expression and/or gain-of-function mutations of the AR[6]
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