Steroid 5α-Reductase Isozymes I and II in Recurrent Prostate Cancer

Abstract

Purpose: Prostate cancer recurs during androgen deprivation therapy despite reduced circulating androgens. We showed that recurrent prostate cancer tissue has testosterone levels similar to androgen-stimulated benign prostate, whereas dihydrotestosterone levels were reduced 82% to 1.45 nmol/L, sufficient for androgen receptor activation. The altered testosterone/dihydrotestosterone ratio in recurrent prostate cancer suggests loss of 5a-reducing capability. The aim of this study was to characterize steroid 5a-reductase isozymes I (S5aRI) and II (S5aRII) in prostate tissues. Experimental Design: A tissue microarray was constructed from 22 recurrent prostate cancer specimens and matched pairs of androgen-stimulated benign prostate and androgen-stimulated prostate cancer from 23 radical prostatectomy specimens. Immunoblots were constructed from eight recurrent prostate cancers, eight androgen-stimulated benign prostate, and eight androgenstimulated prostate cancer specimens. Isozyme expression was examined in microarray sections and immunoblots using S5aRI and S5aRII polyclonal antibodies. Isozyme activities were measured in 12 recurrent prostate cancer, 12 androgen-stimulated benign prostate, and 12 androgenstimulated prostate cancer specimens. Results: Nuclear immunostaining exhibited higher S5aRI expression than S5aRII in recurrent prostate cancer, androgen-stimulated benign prostate, and androgen-stimulated prostate cancers (P < 0.0001); mean expression was 125, 150, and 115 for S5aRI versus 10, 29, and 37 for S5aRII, respectively. Cytoplasmic immunostaining was moderate and similar for both isozymes in the three tissue types (P > 0.05). Immunoblots confirmed immunohistochemistry; S5aRI was expressed in recurrent prostate cancer specimens and S5aRII was not detected. The activity of S5aRI (114.4 pmol/mg epithelial protein/minute) was 3.7-fold higher than S5aRII (30.7 pmol/ mg epithelial protein/minute) in recurrent prostate cancer specimens. Conclusions: Expression levels and isozyme activity shifts from S5aRII toward S5aRI in recurrent prostate cancer. Dual inhibition of S5aRI and S5aRII should reduce dihydrotestosterone biosynthesis and may prevent or delay growth of recurrent prostate cancer.Androgen target cells in peripheral tissues use testosterone to activate androgen receptor, which interacts with androgen response elements in DNA to regulate gene transcription. Alternatively, intracellular testosterone acts as a prohormone that is converted to dihydrotestosterone, a more potent androgen receptor ligand. In the prostate, an intracrine pathway (1) uses the enzyme steroid 5a-reductase (EC 1.3.99.5) to metabolize testosterone to dihydrotestosterone. The adrenal androgen androstenedione is also converted to 5a-reduced androstanedione by steroid 5a-reductase in the prostate (2) and androstenedione has been implicated as a source of dihydrotestosterone in prostate tissue after castration (3).Steroid 5a-reductase is a membrane-associated, NADPHdependent enzyme that catalyzes the irreversible stereospec...

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