Latrophilins as Downstream Effectors of Androgen Receptors including a Splice Variant, AR-V7, Induce Prostate Cancer Progression.

Latrophilins (LPHNs), a group of the G-protein-coupled receptor to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. In the present study, we aimed to determine the role of LPHNs in the progression of prostate cancer. We assessed the actions of LPHNs, including LPHN1, LPHN2, and LPHN3, in human prostate cancer lines via their ligand (e.g., α-LTX, FLRT3) treatment or shRNA infection, as well as in surgical specimens. In androgen receptor (AR)-positive LNCaP/C4-2/22Rv1 cells, dihydrotestosterone considerably increased the expression levels of LPHNs, while chromatin immunoprecipitation assay revealed the binding of endogenous ARs, including AR-V7, to the promoter region of each LPHN. Treatment with α-LTX or FLRT3 resulted in induction in the cell viability and migration of both AR-positive and AR-negative lines. α-LTX and FLRT3 also enhanced the expression of Bcl-2 and phosphorylated forms of JAK2 and STAT3. Meanwhile, the knockdown of each LPHN showed opposite effects on all of those mediated by ligand treatment. Immunohistochemistry in radical prostatectomy specimens further showed the significantly elevated expression of each LPHN in prostate cancer, compared with adjacent normal-appearing prostate, which was associated with a significantly higher risk of postoperative biochemical recurrence in both univariate and multivariable settings. These findings indicate that LPHNs function as downstream effectors of ARs and promote the growth of androgen-sensitive, castration-resistant, or even AR-negative prostate cancer.

GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer.

The precise molecular mechanisms responsible for resistance to cisplatin-based chemotherapy in patients with bladder cancer remain elusive, while we have indicated that androgen receptor (AR) activity in urothelial cancer is associated with its sensitivity. Our DNA microarray analysis in control vs. AR-knockdown bladder cancer sublines suggested that the expression of a GABA B receptor GABBR2 and AR was correlated. The present study aimed to determine the functional role of GABBR2 in modulating cisplatin sensitivity in bladder cancer. AR knockdown and dihydrotestosterone treatment considerably reduced and induced, respectively, GABBR2 expression, and the effect of dihydrotestosterone was at least partially restored by an antiandrogen hydroxyflutamide. A chromatin immunoprecipitation assay further revealed the binding of AR to the promoter region of GABBR2 in bladder cancer cells. Meanwhile, GABBR2 expression was significantly elevated in a cisplatin-resistant bladder cancer subline, compared with control cells. In AR-positive bladder cancer cells, knockdown of GABBR2 or treatment with a selective GABA B receptor antagonist, CGP46381, considerably enhanced the cytotoxic activity of cisplatin. However, no additional effect of CGP46381 on cisplatin-induced growth suppression was seen in GABBR2-knockdown cells. Moreover, in the absence of cisplatin, CGP46381 treatment and GABBR2 knockdown showed no significant changes in cell proliferation or migration. These findings suggest that GABBR2 represents a key downstream effector of AR signaling in inducing resistance to cisplatin treatment. Accordingly, inhibition of GABBR2 has the potential of being a means of chemosensitization, especially in patients with AR/GABBR2-positive bladder cancer.

Comparison of Optic Nerve Sheath Diameter (ONSD) in Low-Pressure Versus Normal Pressure Pneumoperitoneum in Laparoscopic Cholecystectomy: A Randomized Clinical Study.

Background: Low pressure laparoscopic cholecystectomy has been advocated due to reduction in postoperative pain, ventilation problems, hemodynamic complications, and potential for reduction in surgical events. No reported data have been found focusing on the effects of low-pressure laparoscopic cholecystectomy on intracranial pressure (ICP). The aim of this study was to investigate the effect of low-pressure laparoscopic cholecystectomy on intracranial pressure measured by optic nerve sheath diameter (ONSD) in Imam Hossein Medical Center, Tehran, Iran. Methods: The patients classified as American Society of Anesthesiologists physical status I or II undergoing elective laparoscopic cholecystectomy due to benign gallbladder disease were randomly assigned to low-pressure laparoscopy (LPL) group or normal pressure laparoscopy group (NPL). ONSD was measured at 3 different times: (1) before induction of anesthesia; (2) after initiation of gas insufflation; and (3) after the termination of gas insufflation. The collected data were entered into SPSS software (V 24). Data were demonstrated with frequency (percentage) or mean ± standard deviation. We used the Mann-Whitney test to compare the means of continuous variables. The Friedman test was used to compare the mean of variables over time in each of the 2 groups. The significance level in all analyses was considered at ˂0.05. Results: ONSD after the termination of gas insufflation was significantly lower in the LPL group with the mean of 4.97±0.83 mm than the NPL group with the mean of 5.62±1.32 mm (p=0.018). ONSD before induction of anesthesia or immediately after gas insufflation did not differ significantly between LPL and NPL groups. Duration of anesthesia and surgery, mean arterial pressure, the total dose of propofol (p=0.600), and fentanyl (p=0.201) did not show significant differences between the 2 groups. Conclusion: ONSD was lower with low-pressure laparoscopic cholecystectomy after the termination of gas insufflation, which emphasized the neural protective effect of low intraperitoneal pressure. Further studies are needed to evaluate this diagnostic tool in different populations, especially in patients with increased ICP undergoing laparoscopic interventions.