Androgen receptor regulation of the seladin-1/DHCR24 gene: altered expression in prostate cancer.

Prostate cancer (CaP) represents a major leading cause of morbidity and mortality in the Western world. Elevated cholesterol levels, resulting from altered cholesterol metabolism, have been found in CaP cells. Seladin-1 (SELective Alzheimer Disease INdicator-1)/DHCR24 is a recently described gene involved in cholesterol biosynthesis. Here, we demonstrated the androgen regulation of seladin-1/DHCR24 expression, due to the presence of androgen responsive element sequences in its promoter region. In metastatic androgen receptor-negative CaP cells seladin-1/DHCR24 expression and cholesterol amount were reduced compared to androgen receptor-positive cells. In tumor samples from 61 patients who underwent radical prostatectomy the expression of seladin-1/DHCR24 was significantly higher with respect to normal tissues. In addition, in cancer tissues mRNA levels were positively related to T stage. In tumor specimens from 23 patients who received androgen ablation treatment for 3 months before surgery seladin-1/DHCR24 expression was significantly lower with respect to patients treated by surgery only. In conclusion, our study demonstrated for the first time the androgen regulation of the seladin-1/DHCR24 gene and the presence of a higher level of expression in CaP tissues, compared to the normal prostate. These findings, together with the results previously obtained in metastatic disease, suggest an involvement of this gene in CaP.

Combination therapy with rofecoxib and finasteride in the treatment of men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH).

PURPOSE: Cyclooxygenase-2 (COX-2) is expressed in human BPH tissue and displays either a pro-inflammatory effect or a proliferative effect on prostate cells. The aim of this study is to analyze whether combination therapy with rofecoxib, a COX-2 inhibitor, and finasteride offers an advantage compared to finasteride monotherapy in patients with BPH. MATERIALS AND METHODS: This is a single centre unblinded trial. Forty-six consecutive men with LUTS and BPH were entered into the study and were randomized to receive rofecoxib 25mg/day plus finasteride 5mg/day (group B) versus finasteride 5mg/day alone (group A) for 24 weeks. Inclusion criteria included also a prostate size greater than 40 cc. The efficacy and safety of treatments were assessed at baseline and at week 4, 12 and 24. RESULTS: In our population, both treatments (groups A and B) produced statistically significant improvements in total IPSS and Q(max) from baseline during follow-up, although they were very low in particular for the finasteride alone group at 4 weeks. We found that finasteride monotherapy produces very little improvement at the 1 month interval. In comparing group A with group B, a significantly higher improvement in IPSS (p=0.0001) and Q(max) (p=0.03) was obtained in group B at 4 weeks interval (% cases with IPSS reduction >4 points: group B=34.7, group A=0; % cases with Q(max) improvement >3 ml/s: group B=8.7, group A=0), whereas at week 24, the differences between the two treatments were not significant (p>0.05). CONCLUSIONS: In our population, the advantage of the combination therapy compared to finasteride alone is significant in a short-term interval (4 weeks). It can be hypothesized that the association of rofecoxib with finasteride induces a more rapid improvement in clinical results until the effect of finasteride becomes predominant.

Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the Trp64Arg variant of the beta-3-adrenergic receptor.

Thyroid hormone action is an important determinant of energy and glucose metabolism. T4 metabolism is regulated by the deiodinases of which type 2 is expressed in humans in skeletal muscle and brown adipose tissue, where its transcription is stimulated by the beta-3 adrenergic pathway. We performed molecular scanning of the human type 2 deiodinase (DIO2) gene and evaluated a novel variant for associations with obesity and insulin resistance, assessing both the main effect and interaction with the Trp64Arg beta-3--adrenergic receptor (ADRB3) variant. Molecular scanning of DIO2 in 50 obese Caucasians demonstrated a Thr92Ala variant. Association studies in 972 nondiabetic patients, 135 of whom underwent euglycemic-hyperinsulinemic clamps, showed that subjects with the Thr92Ala variant had lower glucose disposal rate (0.54 plus minus 0.02 mg center dot min(-1) center dot kg(-1) fat-free mass Ala92 homozygotes vs. 0.44 plus minus 0.02 Ala92 heterozygotes vs. 0.42 plus minus 0.04 Thr92 homozygotes, P = 0.0088). Association analysis of the entire group showed significant evidence for a synergistic effect between the Thr92Ala DIO2 and Trp64Arg ADRB3 variants on BMI (both variants 34.3 plus minus 0.9 kg/m(2) vs. neither variant 33.1 plus minus 0.4 kg/m(2), P = 0.04 for interaction). To our knowledge, Thr92Ala is the first description of a missense mutation of DIO2. This variant strongly associates with insulin resistance and, in subjects with the Trp64Arg ADRB3 variant, an increased BMI, suggesting an interaction between these two common gene variants.