Intratumoral conversion of adrenal androgen precursors drives androgen receptor‐activated cell growth in prostate cancer more potently than de novo steroidogenesis. Issue 15 (2nd September 2013)

• Record Type: Journal Article
• Authors: Kumagai, Jinpei; Hofland, Johannes; Erkens‐Schulze, Sigrun; Dits, Natasja F.J.; Steenbergen, Jacobie; Jenster, Guido; Homma, Yukio; de Jong, Frank H.; van Weerden, Wytske M.
• Is Part Of: Prostate. Volume 73:Issue 15(2013)
• Page Start: 1636
• Page End: 1650
• Publication Date: 2013-09-02
• Subjects: Prostate -- Diseases -- Periodicals; 616
• DOI: 10.1002/pros.22655
• Languages: English
• ISSNs: 0270-4137

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="pros22655-sec-0001" sec-type="section"> <title>BACKGROUND</title> <p>Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration‐resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR‐driven cell growth is unknown.</p> </sec> <sec id="pros22655-sec-0002" sec-type="section"> <title>METHODS</title> <p>The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)‐regulated cell growth and expression of <italic>PSA</italic>, <italic>FKBP5</italic>, and <italic>TMPRSS2</italic> was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP.</p> </sec> <sec id="pros22655-sec-0003" sec-type="section"> <title>RESULTS</title> <p>In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing <italic>CYP17A1</italic> did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells.</p> </sec> <sec id="pros22655-sec-0004" sec-type="section"> <title>CONCLUSIONS</title> <p>Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth. <italic>Prostate 73: 1636–1650, 2013</italic>. © 2013 Wiley Periodicals, Inc.</p> </sec> </abstract>