Evidence for Involvement of ADP-Ribosylation Factor 6 in Intracellular Trafficking and Release of Murine Leukemia Virus Gag.

Murine leukemia viruses (MuLVs) are simple retroviruses that cause several diseases in mice. Retroviruses encode three basic genes: gag, pol, and env. Gag is translated as a polyprotein and moves to assembly sites where viral particles are shaped by cleavage of poly-Gag. Viral release depends on the intracellular trafficking of viral proteins, which is determined by both viral and cellular factors. ADP-ribosylation factor 6 (Arf6) is a small GTPase that regulates vesicular trafficking and recycling of different types of cargo in cells. Arf6 also activates phospholipase D (PLD) and phosphatidylinositol-4-phosphate 5-kinase (PIP5K) and produces phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). We investigated how Arf6 affected MuLV release with a constitutively active form of Arf6, Arf6Q67L. Expression of Arf6Q67L impaired Gag release by accumulating Gag at PI(4,5)P2-enriched compartments in the cytoplasm. Treatment of the inhibitors for PLD and PIP5K impaired or recovered MuLV Gag release in the cells expressing GFP (control) and Arf6Q67L, implying that regulation of PI(4,5)P2 through PLD and PIP5K affected MuLV release. Interference with the phosphoinositide 3-kinases, mammalian target of rapamycin (mTOR) pathway, and vacuolar-type ATPase activities showed further impairment of Gag release from the cells expressing Arf6Q67L. In contrast, mTOR inhibition increased Gag release in the control cells. The proteasome inhibitors reduced viral release in the cells regardless of Arf6Q67L expression. These data outline the differences in MuLV release under the controlled and overactivated Arf6 conditions and provide new insight into pathways for MuLV release.

Natural Phytochemicals in Bladder Cancer Prevention and Therapy.

Phytochemicals are natural small-molecule compounds derived from plants that have attracted attention for their anticancer activities. Some phytochemicals have been developed as first-line anticancer drugs, such as paclitaxel and vincristine. In addition, several phytochemicals show good tumor suppression functions in various cancer types. Bladder cancer is a malignant tumor of the urinary system. To date, few specific phytochemicals have been used for bladder cancer therapy, although many have been studied in bladder cancer cells and mouse models. Therefore, it is important to collate and summarize the available information on the role of phytochemicals in the prevention and treatment of bladder cancer. In this review, we summarize the effects of several phytochemicals including flavonoids, steroids, nitrogen compounds, and aromatic substances with anticancer properties and classify the mechanism of action of phytochemicals in bladder cancer. This review will contribute to facilitating the development of new anticancer drugs and strategies for the treatment of bladder cancer using phytochemicals.

Is high-dose leuprorelin acetate effective and safe in asian men with prostate cancer? An open-label, non-comparative, multi-center clinical trial.

PURPOSE: Leuprorelin is a well known luteinizing hormone releasing hormone agonist. However, there are insufficient data on the efficacy and safety of high dose leuprorelin acetate, especially in Asian patients with prostate cancer. We aimed to investigate the safety and efficacy of leuprorelin acetate 22.5 mg administered at three-month intervals in patients with prostate cancer. MATERIALS AND METHODS: In an open, prospective clinical trial enrolling 47 patients, we aimed to assess the efficacy and safety of leuprorelin acetate 22.5 mg in treating patients with histologically confirmed prostate cancer. The primary objective of this study was to evaluate the efficacy of the leuprorelin acetate 22.5 mg in producing and maintaining castration levels of testosterone over a 6-month follow-up period and to determine its safety profile. RESULTS: All 42 patients achieved serum testosterone levels within the castration range by 4 weeks. A breakthrough response was observed in one of 36 patients by 8 weeks. However, this patient was medically castrated by 12 weeks. There were no significant prostate-specific antigen (PSA) or testosterone changes according to clinical stage or body mass index. Twenty adverse events (AEs) in 15 of 42 patients (35.7%) were observed during this study. The most common AEs were hot flushes (n=4, 20.0%) with mild intensity, pain (n=2, 10.0%), and infection (n=2, 10.0%). No patient withdrew from the study due to AEs. CONCLUSION: Leuprorelin acetate 22.5 mg was shown to be effective and safe in Asian patients with prostate cancer, even though sexual function decreased.

A preliminary study of the variability in location of the ureteral orifices with bladder filling by fluoroscopic guidance: the gender difference.

BACKGROUND AND PURPOSE: To determine landmarks for stent positioning in both ureteral orifices (UOs) and the gender differences in their location in men and women. PATIENTS AND METHODS: The location of the UO and the bladder neck (BN) was measured fluoroscopically by the intravesical distal location of an open-ended catheter marked with radiopaque materials. We compared the location in men (n = 12) and women (n = 12) with a full bladder (hydrostatic pressure of 50 cmH2O) or an empty bladder. RESULTS: The mean distances from BN to UO in men and women were significantly different both in an empty bladder (2.5 ± 0.4 and 2.1 ± 0.3 cm, respectively) and in a full bladder (2.9 ± 1.0 and 2.3 ± 0.6 cm, respectively). The location of UO was changed by bladder filling in women but not in men. In women, most UOs were found superior to the symphysis pubis (SP) in empty bladder (66.6 %). Most of this location was observed at behind the upper boarder of SP in full bladder of women (75 %). The BN of women was located at the lower level in basal state compared to men. Also, the location of BN was markedly changed by bladder fulling in women (p = 0.04) but not in men. CONCLUSIONS: Significant gender differences were observed in the location of UO and BN. Clinicians should keep in mind the anatomical differences between men and women during fluoroscopic-guided procedure.

Is further evaluation needed for incidental focal uptake in the prostate in 18-fluoro-2-deoxyglucose positron emission tomography-computed tomography images?

OBJECTIVE: The aim of this study was to investigate the frequency of secondary evaluation to detect prostate cancer that was primarily manifested as abnormal hypermetabolism detected by 18-fluoro-2-deoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT). We also evaluated the association of maximum standardized uptake values (SUVmax) on PET/CT with clinicopathologic results. MATERIALS AND METHODS: We evaluated PET/CT reports from a total of 12,037 patients to find cases with abnormal prostate hypermetabolism. Patients with known prostate cancer or a recent prostate procedure were excluded. We analyzed the frequency of secondary evaluations such as digital rectal exams (DRE), levels of serum prostate-specific antigen (PSA), and/or biopsy to confirm prostate cancer. Biopsied patients were categorized into benign and cancer groups. Clinicopathologic characteristics were compared between the groups. RESULTS: Among 12,037 PET/CT images, 184 (1.5%) showed abnormal hypermetabolism in the prostate. Secondary evaluation was carried out in 120 patients. Biopsy was performed in 38 patients and prostate cancer was confirmed in 23 patients. The median serum PSA level was 3.2 and 49.7 ng/mL in the benign group and cancer group, respectively. The SUVmax was higher in the cancer group (5.7 ± 5.1) than in the benign group (4.8 ± 2.7), but the difference was not statistically significant (p = 0.37). In the cancer group, a high serum PSA level (≥ 20 ng/mL) was detected in 78.3% of the patients. The Gleason score was 7 in 34.7% and 8-10 in 56.5% of prostate cancer patients. CONCLUSIONS: Hypermetabolism in the prostate was incidentally detected in 1.5% of patients, and only 65.2% of these patients underwent further evaluation (DRE and/or serum PSA levels). Among cases of incidentally detected hypermetabolism in the prostate, patients with abnormal findings (DRE and/or PSA levels) showed high positivity by biopsy, and more than two-thirds of the positive biopsies showed significant prostate cancer. Therefore, patients with hypermetabolism in the prostate should not be ignored and should be secondarily evaluated by DRE and PSA level.

Expression and localization of aquaporins in benign prostate hyperplasia and prostate cancer.

The aquaporin (AQP) families of water channels are intrinsic membrane proteins that facilitate selective water and small solute movement across the plasma membrane. The purposes of this study were to determine the expression and localization of AQPs in benign prostatic hyperplasia and prostate cancer. Prostatic tissue was collected from patients with benign prostatic hyperplasia or prostate cancer by transurethral resection of the prostate. The expression and cellular localization of the AQPs were determined in the human prostate by Western blot and immunohistochemistry. AQP1, 3, and 9 were expressed in the human prostate. Western blot analysis revealed bands at 28-36 kDa for the AQP1, 3, and 9 proteins. Of these proteins, AQP3 and 9 were expressed in the epithelium. Immunolabeling showed that AQP1 was mainly expressed in the capillaries and venules of the prostate, AQP9 was expressed in the cytoplasm of the epithelium, and AQP3 was mainly associated with the plasma membrane of the prostatic epithelium. Only AQP3 expression was localized in the cell membrane, and expressed AQP3 was translocated to the cytoplasm in prostate cancer. The epithelium in the human prostate expresses AQP3 and 9 proteins, and the capillaries and venules of the prostate express AQP1. Characterizing or modifying the expression of AQP3 may lead to an understanding of the role of the AQPs in human prostatic disease.

HOXB13 promotes androgen independent growth of LNCaP prostate cancer cells by the activation of E2F signaling.

BACKGROUND: Androgen signaling plays a critical role in the development of prostate cancer and its progression. However, androgen-independent prostate cancer cells emerge after hormone ablation therapy, resulting in significant clinical problems. We have previously demonstrated that the HOXB13 homeodomain protein functions as a prostate cancer cell growth suppressor by inhibiting androgen-mediated signals. However, the role of the HOXB13 in androgen-independent growth of prostate cancer cells remains unexplained. RESULTS: In this report, we first demonstrated that HOXB13 was highly overexpressed in hormone-refractory tumors compared to tumors without prostate-specific antigen after initial treatment. Functionally, in an androgen-free environment minimal induction of HOXB13 in LNCaP prostate cancer cells, to the level of the normal prostate, markedly promoted cell proliferation while suppression inhibited cell proliferation. The HOXB13-mediated cell growth promotion in the absence of androgen, appears to be mainly accomplished through the activation of RB-E2F signaling by inhibiting the expression of the p21waf tumor suppressor. Indeed, forced expression of HOXB13 dramatically decreased expression of p21waf; this inhibition largely affected HOXB13-mediated promotion of E2F signaling. CONCLUSIONS: Taken together, the results of this study demonstrated the presence of a novel pathway that helps understand androgen-independent survival of prostate cancer cells. These findings suggest that upregulation of HOXB13 is associated with an additive growth advantage of prostate cancer cells in the absence of or low androgen concentrations, by the regulation of p21-mediated E2F signaling.

Prostate calculi in cancer and BPH in a cohort of Korean men: Presence of calculi did not correlate with cancer risk.

Prostatic calculi are common and are associated with inflammation of the prostate. Recently, it has been suggested that this inflammation may be associated with prostate carcinogenesis. The aim of this study was to investigate the relationship between prostatic calculi and prostate cancer (PCa) in prostate biopsy specimens. We retrospectively analyzed 417 consecutive patients who underwent transrectal ultrasonography (TRUS) and prostate biopsies between January 2005 and January 2008. Based on the biopsy findings, patients were divided into benign prostatic hyperplasia and PCa groups. TRUS was used to detect prostatic calculi and to measure prostate volume. The correlations between PCa risk and age, serum total PSA levels, prostate volume, and prostatic calculi were analyzed. Patient age and PSA, as well as the frequency of prostatic calculi in the biopsy specimens, differed significantly between both the groups (P < 0.05). In the PCa group, the Gleason scores (GSs) were higher in patients with prostatic calculi than in patients without prostatic calculi (P = 0.023). Using multivariate logistic regression analysis, we found that patient age, serum total PSA and prostate volume were risk factors for PCa (P = 0.001), but that the presence of prostatic calculi was not associated with an increased risk of PCa (P = 0.13). In conclusion, although the presence of prostatic calculi was not shown to be a risk factor for PCa, prostatic calculi were more common in patients with PCa and were associated with a higher GS among these men.