Abstract
The enzyme 5α-reductase, which converts testosterone to dihydrotestosterone (DHT), performs key functions in the androgen receptor (AR) signaling pathway. The three isoenzymes of 5α-reductase identified to date are encoded by different genes: SRD5A1, SRD5A2, and SRD5A3. In this study, we investigated mechanisms underlying androgen regulation of 5α-reductase isoenzyme expression in human prostate cells. We found that androgen regulates the mRNA level of 5α-reductase isoenzymes in a cell type–specific manner, that such regulation occurs at the transcriptional level, and that AR is necessary for this regulation. In addition, our results suggest that AR is recruited to a negative androgen response element (nARE) on the promoter of SRD5A3 in vivo and directly binds to the nARE in vitro. The different expression levels of 5α-reductase isoenzymes may confer response or resistance to 5α-reductase inhibitors and thus may have importance in prostate cancer prevention.
Highlights
The multiyear, multistep process of prostate carcinogenesis and its long latency period make prostate cancer ideal for chemoprevention [1]
To identify good model systems for studying the functions of 5areductase isoenzymes, we evaluated the mRNA levels of the 5areductase isoenzymes in different prostate cell lines, including PWR-1E immortalized normal prostatic epithelial cells; BPH-1AR benign prostatic hyperplasia (BPH) cells, which stably express androgen receptor (AR); LAPC-4 and LNCaP androgen-sensitive prostate cancer cells; and C4-2B4 androgen-independent cells
PWR1-E, BPH-1-AR and LAPC-4 cells express wild-type AR, whereas LNCaP and C42B4 cells express a mutant AR, T877A. (The characteristics of these cell lines, including their source, androgen sensitivity, and AR-expression status, are summarized in Table S1.) As Figure 1 illustrates, the mRNA of all three 5a-reductase isoenzymes was detected on qRT-polymerase chain reaction (PCR) analysis of each cell line, indicating that all three are expressed in these cell lines
Summary
The multiyear, multistep process of prostate carcinogenesis and its long latency period make prostate cancer ideal for chemoprevention [1]. Immunohistochemical and polymerase chain reaction (PCR) analyses of human prostate tissues suggest that SRD5A1 and SRD5A2 levels change with prostate cancer development and progression [7,8,9]. In vitro studies have confirmed the 5areductase activity of the more-recently identified SRD5A3 [10], which was overexpressed in hormone-refractory prostate cancer tissues [10,11]. By using a monoclonal antibody, Godoy et al further showed increased level of SRD5A3 protein in the prostate cancer compared to benign prostate tissues [12]. These findings suggested that SRD5A3 may contribute to prostate cancer progression. Mutations of SRD5A3 result in congenital disorders [13,14] and Kahrizi syndrome [15]
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