【特刊综述】雄激素和前列腺疾病

越来越多的文献认同睾酮治疗在性腺机能低下患者中具有促合成代谢作用。而关于老年男性使用外源性雄激素的风险和其对前列腺潜在副作用的研究数据仍然匮乏。老年和性腺机能低下男性接受睾酮治疗是否会加重下尿路症状或加剧、揭露,甚至刺激前列腺癌发展,这一问题使采用睾酮治疗的热情有所减缓,与此同时前列腺疾病被视作睾酮治疗的相对禁忌。雄激素对于前列腺的发育和维护是必要的。无论如何,流行病学研究并没有一致地发现内源性血清雄激素浓度与前列腺疾病风险之间存在正相关。虽然最新研究显示5α还原酶抑制剂降低了患低级别前列腺癌的风险,说明抑制雄激素代谢有利于前列腺健康,但是对于高级别前列腺癌并没有类似作用,因此对这些药物化学预防的真正临床效益提出了质疑。鉴于缺乏大样本随机试验,很难了解如何最好地研究雄激素和前列腺疾病发展之间的关系。越来越多研究质疑雄激素在血清中的变化与其在前列腺激素环境中的变化有类似效应或者改变腺体内雄激素的调节过程。需要长期的干预性研究来真正证实雄激素对前列腺组织和疾病风险的操控。然而,现有数据认为恢复血清雄激素至生理水平并不会触发前列腺疾病。     

Androgens stimulate both growth rate and epidermal growth factor receptor activity of the human prostate tumor cell LNCaP

LNCaP cells (derived from a lymph node carcinoma of the human prostate) contain androgen receptors and show androgen-responsive growth in vitro. Maximal effects on growth were seen at 0.1 nM of the synthetic androgen R1881 or 0.2 nM of epidermal growth factor (EGF); both compounds independently increased the growth rate 2-3 times. EGF-receptors were measured after 6 days culture in the presence or absence of 0.1 nM R1881. A 2.3-fold increase in receptor number/cell was found when binding was measured at 0 degrees C (from 12,500 to 28,900 sites/cell in stimulated cells). The kD value (0.45 nM) was not affected by androgen treatment. The increase of EGF-receptor activity was first observed between 6 and 12 h after exposure to androgen. It is concluded that LNCaP cells are sensitive to low concentrations of EGF (or EGF-like compounds) and that one of the mechanisms involved in androgen action on these cells is an increase of EGF-receptor expression at the cell surface.     

Castration-induced changes in morphology,androgen levels,and proliferative activity of human prostate cancer tissue grown in athymic nude mice

The transplantable human prostate tumor lines PC-82 and PC-EW regress after androgen depletion. The castration-induced decline in tumor volume was faster in the PC-EW tumor (half-life 6 days) than in the PC-82 tumor (half-life 18 days), despite similar castrate androgen levels of less than 3 pmollg tissue. Androgen ablation of the PC-82 tumor induced a wave of apoptosis, whereas in the PC-EW tumor, necrotic cell death was predominantly observed. The proliferative activity (BrdU index) of PC-82 and PC-EW tumor tissue declined from 3% to less than 1% after castration. After androgen depletion, some proliferative activity remained, the major part of which was localized in the (murine) stromal compartment of the tumors. In contrast to the PC-EW tumors, regrowth of androgen-ablated PC-82 tumors was rapidly induced by androgen resubstitution. The differences in response of these tumor models to androgen depletion and repletion appear to be related to the putative involvement of different cell death pathways. The role of the stroma in these processes is unclear. © 1993 Wiley-Liss, Inc.     

Androgens upregulate aquaporin 9 expression in the prostate

Objectives: Aquaporins (AQP) function as selective pores allowing water, glycerol and other small solutes to pass through the cell membrane. We previously reported that AQP are expressed in the prostates of both humans and rats. The present study investigated the androgen‐dependent expression of AQP9 in the prostate in vivo and in vitro. Methods: Rat ventral prostate tissue specimens and a normal human prostatic epithelial cell line (PNT2) were used. AQP9 messenger ribonucleic acid (mRNA) and protein expression were examined using real‐time polymerase chain reaction, Western blotting and immunohistochemical methods. Androgen modulation was achieved by surgical castration, treatment with testosterone propionate (5 µg/g bodyweight) or bicalutamide (20 µg/g bodyweight), and the ribonucleic acid interference (RNAi) method of the androgen receptor (AR). The synthetic small interfering RNA was transfected into PNT2 at a concentration of 10 nM, and the RNAi effect was evaluated using a Western blotting analysis. Results: AQP9 mRNA and protein were expressed in the rat prostate. Surgical castration or bicalutamide treatment significantly decreased their expression. In addition, the treatment with testosterone propionate after castration restored the expression to the level of the controls. An RNAi experiment in PNT2 also decreased the expression. Conclusions: AQP9 expression in the prostate is controlled by androgens.     

Androgens and prostate cancer

Over 60 years ago Huggins and Hodges demonstrated the importance of androgens and prostate cancer. Since then, significant research has revealed that this relationship is multi-faceted and is interwoven with different signaling cascades and protein coactivators. The complex interrelationship between hormone and cancer is best exemplified by the recurrence and progression of prostate cancer after hormonal therapy to a lethally resistant phenotype despite initially encouraging therapeutic responses. If we are to significantly improve survival with novel therapies, further understanding of the emergence of this resistant phenotype is essential. The purpose of this article is to review the mechanisms of androgen action and its relation to hormonal therapy and mechanisms of hormonal resistance.     

Longitudinal evaluation of serum androgen levels in men with and without prostate cancer

Androgens are thought to play a role in the pathogenesis of prostate cancer. We evaluated androgen levels in 3 age-matched groups of men who were part of the Baltimore Longitudinal Study of Aging: 1) 16 men with no prostatic disease by urologic history and exam (control group); 2) 20 men with a histologic diagnosis of benign prostatic hyperplasia (BPH) who had undergone simple prostatectomy; and 3) 20 men with a histologic diagnosis of prostate cancer (16 with local/regional cancer, and 4 with metastatic cancer). Luteinizing hormone (LH), total testosterone (T), and free T were measured on stored AM sera by radioimmunoassay (RIA). Free T was also calculated from the measured concentrations of total T and sex hormone binding globulin (SHBG). The median number of repeated sex steroid measurements ranged from 6–9 over a period from 7–25 years prior to the diagnosis of prostate disease. There were no significant differences in age-adjusted LH, total T, SHBG, or calculated free T levels among the groups at 0–5, 5–10, and 10–15 years before diagnosis. These data suggest that there are no measurable differences in serum testosterone levels among men who are destined to develop prostate cancer and those without the disease. © 1995 Wiley-Liss, Inc.     

Studies on serum androgen changes in prostate cancer patients after castration

Aim: To observe the serum androgen changes in patients with prostate cancer (PCa) before and after castration. Methods: Serum testosterone (T), free testosterone (FT) and dihydrotest-osterone (DHT) were determined with radioimmunoassay in 16 cases with PCa one week before and on day 5 after castration. Results: After castration, the serum T, FT and DHT levels significantly declined by 92.27 %, 92.26 % and 58.36 %, respectively, as compared with the pre-castration values (P<0.01). Conclusion: After castration, most T and FT were deprived, while DHT only declined 58.36 %. Androgen receptor competitor should still be administered to antagnize the action of the remaining androgens.     

Effects of bortezomib in sensitizing human prostate cancer cell lines to NK-mediated cytotoxicity

The proteasome inhibitor, bortezomib, has been demonstrated to sensitize tumor cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Natural killer (NK) cells represent potent antitumor effector cells. They also express TRAIL. Therefore, we investigated whether bortezomib could sensitize tumor cells to NK cell-mediated killing, and have the same effect in human prostate cancer cell lines (LNCaP and DU145). We found that bortezomib strongly inhibits proliferation in both cell lines. Furthermore, compared with LNCaP cells, DU145 cells are more sensitive to bortezomib-induced apoptosis. However, bortezomib is unable to sensitize these two cell lines to NK cell-mediated killing in short-term assays. In long-term assays, we found that killing mediated by activated NK cells following bortezomib treatment leads to greater antitumor effects than either treatment alone. In addition, treatment with bortezomib causes these cells to upregulate apoptosis-related mRNA as well as death receptors and downregulate the major histocompatibility class (MHC)-I molecule on the cell surface of DU145 cells. In contrast, LNCaP cells are not sensitized by this treatment. Death receptors and the MHC-I molecule did not change in this cell line. These data suggest that bortezomib can be used to sensitize prostate cancer cells to NK cell-mediated killing and improve current cancer therapies. This therapeutic strategy may be more effective in patients with androgen-insensitive prostate cancer.     

环巴胺对人前列腺癌LNCaP细胞增殖和凋亡作用及对PCA3基因表达的影响

目的:探讨环巴胺对人前列腺癌LNCaP细胞增殖和凋亡的作用及对PCA3基因表达的影响。方法:不同浓度环巴胺(1、5、10、15μmol/L)干预LNCaP细胞,以只加入RPMI 1640培养液为空白对照组,分别在不同作用时间(24、48、72h),用MTT法检测其对细胞增殖的抑制、流式细胞术观察细胞凋亡率变化、Hoechst染色观察凋亡细胞形态变化、实时荧光定量逆转录聚合酶链反应(FQ-RT-PCR)观察对PCA3基因表达的影响。结果:5、10、15μmol/L环巴胺对LNCaP细胞增殖均有显著抑制作用,与空白对照组相比差异有显著性(P0.01),10μmol/L组于48h达到半数抑制量(IC50);10、15μmol/L组24、48、72hLNCaP细胞的凋亡率分别为37.21%、57.38%、57.98%和21.16%、71.31%、72.90%,与空白对照组相比差异均有显著性(P0.01)。随着环巴胺浓度增大和作用时间的延长,LNCaP细胞凋亡显著增加。PCA3基因的表达随着环巴胺浓度的上升呈现明显的递减趋势,较空白对照组显著降低(P0.01)。浓度为10μmol/L时,不同作用时间PCA3基因的表达均极低。结论:环巴胺浓度为10、15μmol/L作用48、72h时能够明显抑制LNCaP细胞的增殖,诱导细胞凋亡,并显著下调LNCaP细胞PCA3基因的表达。     

Effects of galectin-3 expression on growth and tumorigenicity of the prostate cancer cell line LNCaP.

BACKGROUND: Galectin-3 is a beta-galactoside-binding vertebrate lectin. In human prostate cancer, galectin-3 expression has been shown to decrease with progression of disease. In the present study, we further investigated the role of galectin-3 in this malignancy by examining the phenotype of galectin-3-transfected prostate cancer cells. METHODS: Stably transfected galectin-3-expressing cell lines were developed from the prostate cancer cell line LNCaP, which does not constitutively express this molecule. Transfected cells lines were analyzed for alterations in morphology and growth rates, and for ability to form tumors in nude mice. RESULTS: Morphologically, when compared to the parental LNCaP cells, the galectin-3 transfectants had broader, flatter cell bodies, shorter and less finely branched dendritic processes, and large nuclei with pronounced and often multiple nucleoli. The galectin-3 lines were found to proliferate at a slower rate in vitro than either the vector control-transfected lines or parental LNCaP. When injected subcutaneously in nude mice, four of six galectin-3 lines formed tumors at a slower rate than control lines. Twenty-four tumors that formed from the transfected cell lines were examined by immunohistochemistry for galectin-3 expression. Only one tumor was found to express galectin-3, suggesting that the transfected cells which formed tumors were those which successfully down-regulated galectin-3 expression. CONCLUSIONS: In contrast to an apparent stimulatory role in some tumor types, galectin-3 is an inhibitory molecule for prostate cancer.