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Altered androgen-receptor (AR) expression and/or constitutively active AR are commonly associated with prostate cancer (PCa) progression. Targeting AR remains a focal point for designing new strategy of PCa therapy. Here, we have shown that DAB2IP, a novel tumor suppressor in PCa, can inhibit AR-mediated cell growth and gene activation in PCa cells via distinct mechanisms. DAB2IP inhibits the genomic pathway by preventing AR nuclear translocation or phosphorylation and suppresses the non-genomic pathway via its unique functional domain to inactivate c-Src. Also, DAB2IP is capable of suppressing AR activation in an androgen-independent manner. In addition, DAB2IP can inhibit several AR splice variants showing constitutive activity in PCa cells. In DAB2IP(-/-) mice, the prostate gland exhibits hyperplastic epithelia, in which AR becomes more active. Consistently, DAB2IP expression inversely correlates with AR activation status particularly in recurrent or metastatic PCa patients. Taken together, DAB2IP is a unique intrinsic AR modulator in normal cells, and likely can be further developed into a therapeutic agent for PCa.

Loss of DAB2IP, a novel tumor suppressor gene, is associated with the high risk of aggressive prostate cancer (PCa). Previously, we reported that DAB2IP modulated androgen receptor activation in the development of castration-resistant PCa; however, its direct action on the failure of androgen deprivation therapy (ADT) remains largely unknown. In this study, we showed that DAB2IP knockdown could significantly enhance in vitro growth and colony formation of PCa cells following ADT as well as tumorigenicity in pre-castrated nude mice. In addition, DAB2IP loss stabilized mitochondrial transmembrane potential, prevented release of cytochrome c, Omi/HtrA2 and Smac from the mitochondria to the cytoplasm and inhibited intrinsic apoptosis induced by ADT. Mechanistically, DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. Moreover, the luminal epithelia in DAB2IP−/− mice with more activated STAT3 and survivin expression were resistant to castration-induced apoptosis. Consistently, DAB2IP expression inversely correlated with STAT3 phosphorylation and survivin expression in PCa patients. Together, our data indicate that DAB2IP loss reprograms intracellular signal transduction and anti-apoptotic gene expression, which potentiates PCa cell survival from ADT-induced cell death.

To evaluate the efficacy of Silodosin as a medical expulsive therapy of ureteral stones, we searched PubMed, EMBASE, the Cochrane Library, and CBM up to June 2015. All randomized controlled trials (RCTs) were identified in which patients were randomized to receive Silodosin versus placebo or other therapies for ureteral stones. Outcome measures assessed were overall stone expulsion rate (primary) and expulsion time, analgesics times, and the incidence of additional treatment and regarding treatment complications (secondary). Two authors independently assessed study quality and extracted data. All data were analyzed using RevMan 5.3. Seven RCTs with a total of 1035 patients met the inclusion criteria. The pooled meta-analysis showed a significant improvement in stone clearance with Silodosin (Silodosin versus placebo, OR ¼1.69, 95% CI [1.19-2.40], p ¼ 0.003; Silodosin versus tamsulosin, OR ¼2.82, 95% CI [1.79-4.44], p < 0.00001). According to the size and location of ureteral stone, the pooling effects of Silodosin were analyzed, with a meaningful expulsion rate in distal ureteral stone when the size was 5-10 mm. In addition, a shorter expulsion time, fewer analgesics times, and additional treatments were observed. The common side effect was retrograde ejaculation. In summary, Silodosin appears to be more effective than either placebo or tamsulosin. Within the limits of available data, highquality multicenter RCTs are needed to thoroughly evaluate the outcome in the future. ARTICLE HISTORY