Titus Mark A, Gregory Christopher W, Ford O Harris, Schell Michael J, Maygarden Susan J, Mohler James L
Department of Pathology and Laboratory Medicine, Surgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7295, USA.
Clin Cancer Res. 2005 Jun 15;11(12):4365-71. doi: 10.1158/1078-0432.CCR-04-0738.
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 5alpha-reducing capability. The aim of this study was to characterize steroid 5alpha-reductase isozymes I (S5alphaRI) and II (S5alphaRII) in prostate tissues.
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 androgen-stimulated prostate cancer specimens. Isozyme expression was examined in microarray sections and immunoblots using S5alphaRI and S5alphaRII polyclonal antibodies. Isozyme activities were measured in 12 recurrent prostate cancer, 12 androgen-stimulated benign prostate, and 12 androgen-stimulated prostate cancer specimens.
Nuclear immunostaining exhibited higher S5alphaRI expression than S5alphaRII in recurrent prostate cancer, androgen-stimulated benign prostate, and androgen-stimulated prostate cancers (P < 0.0001); mean expression was 125, 150, and 115 for S5alphaRI versus 10, 29, and 37 for S5alphaRII, respectively. Cytoplasmic immunostaining was moderate and similar for both isozymes in the three tissue types (P > 0.05). Immunoblots confirmed immunohistochemistry; S5alphaRI was expressed in recurrent prostate cancer specimens and S5alphaRII was not detected. The activity of S5alphaRI (114.4 pmol/mg epithelial protein/minute) was 3.7-fold higher than S5alphaRII (30.7 pmol/mg epithelial protein/minute) in recurrent prostate cancer specimens.
Expression levels and isozyme activity shifts from S5alphaRII toward S5alphaRI in recurrent prostate cancer. Dual inhibition of S5alphaRI and S5alphaRII should reduce dihydrotestosterone biosynthesis and may prevent or delay growth of recurrent prostate cancer.
尽管循环雄激素水平降低，但前列腺癌在雄激素剥夺治疗期间仍会复发。我们发现复发性前列腺癌组织中的睾酮水平与雄激素刺激的良性前列腺相似，而二氢睾酮水平降低了82%，至1.45 nmol/L，这一水平足以激活雄激素受体。复发性前列腺癌中睾酮/二氢睾酮比例的改变提示5α-还原能力丧失。本研究的目的是对前列腺组织中的类固醇5α-还原酶同工酶I（S5αRI）和II（S5αRII）进行表征。
从22个复发性前列腺癌标本以及23个根治性前列腺切除术标本中配对的雄激素刺激的良性前列腺和雄激素刺激的前列腺癌构建组织微阵列。从8个复发性前列腺癌、8个雄激素刺激的良性前列腺和8个雄激素刺激的前列腺癌标本构建免疫印迹。使用S5αRI和S5αRII多克隆抗体在微阵列切片和免疫印迹中检测同工酶表达。在12个复发性前列腺癌、12个雄激素刺激的良性前列腺和12个雄激素刺激的前列腺癌标本中测量同工酶活性。
在复发性前列腺癌、雄激素刺激的良性前列腺和雄激素刺激的前列腺癌中，核免疫染色显示S5αRI的表达高于S5αRII（P < 0.0001）；S5αRI的平均表达分别为125、150和115，而S5αRII分别为10、29和37。在三种组织类型中，两种同工酶的细胞质免疫染色均为中等且相似（P > 0.05）。免疫印迹证实了免疫组化结果；在复发性前列腺癌标本中检测到S5αRI的表达，未检测到S5αRII的表达。在复发性前列腺癌标本中，S5αRI的活性（114.4 pmol/mg上皮蛋白/分钟）比S5αRII（30.7 pmol/mg上皮蛋白/分钟）高3.7倍。
在复发性前列腺癌中，表达水平和同工酶活性从S5αRII向S5αRI转变。对S5αRI和S5αRII的双重抑制应可减少二氢睾酮的生物合成，并可能预防或延缓复发性前列腺癌的生长。
