The AR/NCOA1 axis regulates prostate cancer migration by involvement of PRKD1.

Due to the urgent need for new prostate cancer (PCa) therapies, the role of androgen receptor (AR)-interacting proteins should be investigated. In this study we aimed to address whether the AR coactivator nuclear receptor coactivator 1 (NCOA1) is involved in PCa progression. Therefore, we tested the effect of long-term NCOA1 knockdown on processes relevant to metastasis formation. [(3)H]-thymidine incorporation assays revealed a reduced proliferation rate in AR-positive MDA PCa 2b and LNCaP cells upon knockdown of NCOA1, whereas AR-negative PC3 cells were not affected. Furthermore, Boyden chamber assays showed a strong decrease in migration and invasion upon NCOA1 knockdown, independently of the cell line's AR status. In order to understand the mechanistic reasons for these changes, transcriptome analysis using cDNA microarrays was performed. Protein kinase D1 (PRKD1) was found to be prominently up-regulated by NCOA1 knockdown in MDA PCa 2b, but not in PC3 cells. Inhibition of PRKD1 reverted the reduced migratory potential caused by NCOA1 knockdown. Furthermore, PRKD1 was negatively regulated by AR. Immunohistochemical staining of PCa patient samples revealed a strong increase in NCOA1 expression in primary tumors compared with normal prostate tissue, while no final conclusion could be drawn for PRKD1 expression in tumor specimens. Thus, our findings directly associate the AR/NCOA1 complex with PRKD1 regulation and cellular migration and support the concept of therapeutic inhibition of NCOA1 in PCa.

Fluorescence Guided Targeted Pelvic Lymph Node Dissection for Intermediate and High Risk Prostate Cancer.

PURPOSE: We investigated whether visualization of the drainage system of the prostate by free indocyanine green would lead to identification of all or even more lymph node metastases detected by super-extended pelvic lymph node dissection in an intermediate and high risk patient population with prostate cancer. MATERIALS AND METHODS: A total of 38 consecutive men with intermediate or high risk prostate cancer according to the D'Amico criteria underwent fluorescence targeted pelvic lymph node dissection during laparoscopic radical prostatectomy. Super-extended pelvic lymph node dissection was added as the control. Patients with neoadjuvant hormonal therapy, macroscopic lymph node involvement or prior transurethral prostate resection were excluded from study. Statistical descriptive methods, and the chi-square test and independent t-test were used to analyze data. RESULTS: Mean patient age was 64.9 years (range 46 to 74) and mean preoperative prostate specific antigen was 13.8 ng/ml (range 0.3 to 44). A total of 23 (60.5%) and 15 cases (39.5%) were classified as intermediate and high risk, respectively. Fluorescence stained nodes were found on each side in all except 1 patient. A total of 700 lymph nodes (mean ± SD 18.4 ± 8.2 per patient) were removed, of which 531 (75% of all nodes) were fluorescence stained (mean 14 ± 8.07 per patient). Lymph node metastases were found in 15 patients (39.5%). Two patients (5.3%) had a solitary micrometastasis and 3 (7.9%) had nodes containing isolated tumor cells. Metastases were found outside the extended pelvic lymph node dissection template in 5 of 15 patients (33.3%). Three of those 5 patients attained a prostate specific antigen nadir of less than 0.1 ng/ml 6 weeks postoperatively. Fluorescence targeted pelvic lymph node dissection showed superior sensitivity and negative predictive value compared to extended and super-extended pelvic lymph node dissection to detect lymph node metastasis. CONCLUSIONS: Fluorescence targeted pelvic lymph node dissection allows for the lymphatic drainage of the prostate to be identified with great reliability. Since only the nodes draining the prostate are removed, the absolute number of removed nodes is decreased while diagnostic accuracy is increased.