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Supplementary Data from High-Density Lipoprotein Induces Proliferation and Migration of Human Prostate Androgen–Independent Cancer Cells by an ABCA1-Dependent Mechanism

The continence self-management programme fee (CSPF) for hospitalized patients was revised in 2020 to include those receiving consistent care on an out-patient basis. We extracted candidate patients for CSPF on an out-patient basis (out-patient candidates hereafter) from those for whom-CSPF had been calculated during hospitalization at our hospital, and defined those who had undergone a medical examination related to continence care as out-patient calculation candidates. Of the 956 patients for whom CSPF had been calculated during hospitalization, 482 patients (50%) were out-patient candidates ; 275 (54%) and 169 (33%) of whom were seen in the urology and neurosurgery departments, respectively. Of the 482 out-patient candidates, 238 (49%) were out-patient calculation candidates ; 197 (83%) and 14 (6%) of whom were seen in the urology and neurosurgery departments, respectively. Forty-two and 41 of the calculation candidates were cases of benign prostatic hyperplasia and bladder cancer, respectively. The CSPF was actually processed 93 times for 78 of the 482 out-patient candidates (16%). There were various obstacles in the current system of calculating the fees to realize consistent care from hospitalization to out-patient care.

Background: There are some reports about the antitumor effects of statins in these days. Statins decrease the level of cholesterol in the blood by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Inhibition of this enzyme decreases intracellular cholesterol synthesis. Thus, the expression of low-density lipoprotein receptor (LDLr) is increased to import more cholesterol from the bloodstream. In this study, we assessed the effects of statins on the proliferation of prostate cancer cells, and studied the relationship between the expression of LDLr and the effects of statins. Methods: Simvastatin was used in the experiments. We studied the effect of simvastatin on PC-3 and LNCaP cell proliferation using the MTS assay, and evaluated the expression of LDLr after administration of simvastatin by quantitative polymerase chain reaction and Western blotting. Intracellular cholesterol levels in the prostate cancer cells were measured after administration of simvastatin. Furthermore, small interfering RNA (siRNA) was used to knockdown the gene expression of LDLr. Results: In PC-3 cells, simvastatin inhibited cell proliferation. In LNCaP cells, only a high concentration of simvastatin (100μM) inhibited cell proliferation. In LNCaP cells, the protein level of LDLr was increased by simvastatin. In PC-3 cells, the protein levels of LDLr were unregulated. In PC-3 cells, but not in LNCaP cells, intracellular cholesterol levels were significantly decreased by simvastatin. After knocking down LDLr expression by siRNA, intracellular cholesterol levels were decreased, and cell proliferation was inhibited by simvastatin in LNCaP cells. Conclusion: Simvastatin inhibited prostate cancer cell growth by decreasing cellular cholesterol and could be more effective in androgen-independent prostate cancer, where there is loss of regulation of LDLr expression. LDLr was shown to play an important role in the statin-induced inhibition of prostate cancer cell proliferation. These results suggest that future studies evaluating the cholesterol-lowering effects of statin may lead to new approaches to the prevention and treatment of prostate cancer.

Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment.

Statins have become of interest in research due to their anticancer effects. However, the exact mechanism of their anticancer properties remains unclear. The authors previously reported that statins decrease intracellular cholesterol levels in androgen-independent prostate cancer cells. In de novo androgen synthesis, cholesterol is the primary material and certain enzymes have important roles. The present study aimed to determine whether simvastatin alters the expression of androgen synthesis-associated enzymes in androgen-independent prostate cancer cells. A novel combination therapy of statins and other drugs that inhibit the overexpression of enzymes involved in androgen synthesis was explored. The cytotoxicity of simvastatin and meclofenamic acid was assessed in prostate cancer cells using MTS and migration assays. Testosterone and dihydrotestosterone concentrations in the culture medium were measured using liquid chromatography-tandem mass spectrometry. RAC-α-serine/threonine-protein kinase (Akt) phosphorylation was detected by western blot analysis. Following treatment with simvastatin, aldo-keto reductase family 1 member C3 (AKR1C3) expression increased in PC-3 (>60-fold) and LNCaP-LA cells, however not in 22Rv1 cells. Small interfering (si)RNA was used to clarify the effects of AKR1C3 expression. The reduction in AKR1C3 expression in PC-3 cells following siRNA transfection was not associated with basal cell proliferation and migration; however, treatment with simvastatin decreased cell proliferation and migration. The combination of simvastatin and meclofenamic acid, an AKR1C3 inhibitor, further enhanced the inhibition of cell proliferation and migration compared with treatment with either drug alone. Furthermore, treatment with simvastatin attenuated insulin-like growth factor 1-induced Akt activation; however, the combination of simvastatin and meclofenamic acid further inhibited Akt activation. These results suggest that the combination of simvastatin and meclofenamic acid may be an effective strategy for the treatment of castration-resistant prostate cancer.

Mammalian target of rapamycin inhibitor has exhibited promising anticancer activity for the treatment of renal cell carcinoma (RCC). However, many patients acquire resistance to therapeutic agents leading to treatment failure. The objective of this study was to determine whether treatment with YM155, a novel small molecule inhibitor of survivin, could reverse rapamycin resistance in a rapamycin-resistant RCC. We induced a rapamycin-resistant clear cell carcinoma cell line (Caki-1-RapR). We showed that survivin gene expression was significantly up-regulated in Caki-1-RapR compared with that in its parent cells (Caki-1). Therefore, we hypothesized that targeting of survivin in Caki-1-RapR could reverse the resistant phenotype in tumor cells, thereby enhancing the therapeutic efficacy of rapamycin. We used both in vitro and in vivo models to test the efficacy of YM155 either as a single agent or in combination with rapamycin. In Caki-1-RapR cells, YM155 significantly decreased survivin gene and protein expression levels and cell proliferation in a dose-dependent manner in vitro. In addition, YM155 treatment significantly reversed rapamycin resistance in cancer cells. In a nude mouse tumor xenograft model, YM155 significantly inhibited the growth of Caki-1-RapR tumor. In addition, YM155 significantly enhanced the antitumor effects of rapamycin in Caki-1-RapR tumor. Our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells, thereby enhancing the effectiveness of molecular target therapy in RCC.

Aim: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reverses statin resistance in statin-resistant renal cell cancer (RCC). Materials and Methods: We induced simvastatin resistance in a renal clear cell carcinoma cell line (Caki-1-staR). In vitro and in vivo models were used to test the efficacy of YM155 and simvastatin. Results: Survivin gene expression was significantly stronger in Caki-1-staR cells than in its parent cells (Caki-1). In Caki-1-staR cells, YM155 significantly reduced expression of survivin gene and cell proliferation in a dose-dependent manner. Treatment with YM155 significantly reversed simvastatin resistance in Caki-1-staR cells. YM155 significantly inhibited the growth of Caki-1-staR tumors in a nude mouse tumor xenograft model. Furthermore, YM155 significantly enhanced the antitumor effects of simvastatin on Caki-1-staR tumors. Conclusion: Our results indicate that inhibition of survivin by YM155 overcomes statin resistance in RCC cells.

Background/Aim: Recent studies have shown that an early prostate-specific antigen (PSA) response to androgen receptor (AR)-targeting agents in metastatic castration-resistant prostate cancer (mCRPC) is associated with a better prognosis. We analyzed early PSA response to enzalutamide and oncological outcomes to study their prognostic significance in the Japanese population. Patients and Methods: Fifty-one patients with mCRPC (26 of pre-docetaxel and 25 of post-docetaxel status) were treated with enzalutamide. The PSA progression-free survival (PFS), radiographic PFS (rPFS) and overall survival (OS) were assessed. The association of rPFS and OS in patients with an early PSA response at 4 weeks after commencement of enzalutamide was studied. Results: Early PSA responses were significantly associated with a longer rPFS (median of 47.9 vs. 20.1 weeks, p

A 41-year-old man with a history of cloacal exstrophy presented to a local clinic with abdominal pain and bowel sounds. He was noted to have pain at the site of scarring due to cloacal exstrophy and a laceration at its center, which was stained with feces. He was referred to our department because of an enterocutaneous fistula. Skin biopsy of the neoplastic lesion at this site led to a diagnosis of squamous cell carcinoma. Computed tomography showed tumor invasion of the ileum and right inguinal lymph node enlargement. We performed tumor resection, partial enterectomy, intestinal anastomosis, abdominal wall reconstruction with a left pedicled anterolateral thigh flap, split-thickness skin grafting, and right inguinal lymph node biopsy. Histopathological examination revealed cancer growth, invasion, and pearl formation in the lymph nodes, leading to a diagnosis of abdominal squamous cell carcinoma with metastasis to the inguinal lymph nodes. The skin graft took well, and the patient was discharged. He is scheduled for right inguinal lymph node dissection at a later date.

BACKGROUND High fat diets are known to be a risk factor for prostate cancer. In this study, we investigated the effect of high fat diet on mouse prostate gene expression. METHODS C57BL/6J mice were fed either a control or high fat diet for 12 weeks. Microarray analyses were performed on mouse ventral prostate (VP) and dorsolateral prostate (DLP), followed by canonical pathway analysis and regulatory network identification. mRNA changes were confirmed by real time PCR. RESULTS Approximately 2,125, and 1,194 genes responded significantly to the high fat diet in VP, DLP, respectively. Pathways and networks related to oxidative stress, glutathione metabolism, NRF-mediated oxidative stress response and NF-kappaB were all differentially regulated by high fat diet. Glutathione peroxidase 3 (GPx3) mRNA levels were decreased by approximately twofold by high fat diet in all three prostate lobes. In human non-transformed prostate cells (PrSC, PrEC, and BPH-1), cholesterol loading decreased GPx3 expression, and increased H2O2 levels of culture medium. Troglitazone increased GPx3 expression in three normal prostate cells, and decreased H2O2 levels. In addition, troglitazone attenuated cholesterol-induced H2O2 increase. Tissue from prostate cancer biopsies had decreased GPx3 mRNA and its level was inversely related to the Gleason score. CONCLUSIONS High fat diet alters pathways related to many genes concerned with oxidative stress. GPx3, a gene identified by this analysis, was found to be down-regulated by high fat diet and appears be decreased in human prostate cancers, suggesting that GPx3 may have a possible role in modulating carcinogenesis. Prostate 71:1499–1509, 2011. © 2011 Wiley-Liss, Inc.

Androgen deprivation therapy for prostate cancer leads to a significant increase of high-density lipoprotein (HDL), which is generally viewed as beneficial, particularly for cardiovascular disease, but the effect of HDL on prostate cancer is unknown. In this study, we investigated the effect of HDL on prostate cancer cell proliferation, migration, intracellular cholesterol levels, and the role of cholesterol transporters, namely ABCA1, ABCG1, and SR-BI in these processes. HDL induced cell proliferation and migration of the androgen-independent PC-3 and DU145 cells by a mechanism involving extracellular signal-regulated kinase (ERK) 1/2 and Akt, but had no effect on the androgen-dependent LNCaP cell, which did not express ABCA1 unlike the other cell lines. Treatment with HDL did not significantly alter the cholesterol content of the cell lines. Knockdown of ABCA1 but not ABCG1 or SR-BI by small interfering RNA (siRNA) inhibited HDL-induced cell proliferation, migration, and ERK1/2 and Akt signal transduction in PC-3 cells. Moreover, after treatment of LNCaP cells with charcoal-stripped fetal bovine serum, ABCA1 was induced ∼10-fold, enabling HDL to induce ERK1/2 activation, whereas small interfering RNA knockdown of ABCA1 inhibited HDL-induced ERK1/2 activation. Simvastatin, which inhibited ABCA1 expression in PC-3 and DU145 cells, attenuated HDL-induced PC-3 and DU145 cell proliferation, migration, and ERK1/2 and Akt phosphorylation. In human prostate biopsy samples, ABCA1 mRNA expression was ∼2-fold higher in the androgen deprivation therapy group than in subjects with benign prostatic hyperplasia or pretreatment prostate cancer groups. In summary, these results suggest that HDL by an ABCA1-dependent mechanism can mediate signal transduction, leading to increased proliferation and migration of prostate cancer cells. Mol Cancer Res; 8(9); 1284–94. ©2010 AACR.

Recently, statins have been being studied for their proapoptic and antimetastatic effects. However, the exact mechanisms of their anticancer action are still unclear. Dolichyl phosphate is a nonsterol isoprenoid derivative in the mevalonate pathway that affects the expression of the Insulin-like growth factor 1 receptor (IGF-1R). IGF-1R activation is required for prostate cell proliferation; therefore, IGF-1R inhibitory agents may be of preventive and/or therapeutic value. In this study, the effects of simvastatin on IGF-1R signaling in prostate cancer PC-3 cells were examined. Simvastatin suppressed proliferation and induced apoptosis of PC-3, and the expression of IGF-1R was suppressed by simvastatin. Knockdown of IGF-1R by siRNA led to inhibition of proliferation of PC-3. Simvastatin also inhibited IGF-1-induced activation of both ERK and Akt signaling and IGF-1-induced PC-3 cell proliferation. Our results suggest statins are potent inhibitors of the IGF-1/IGF-1R system in prostate cancer cells and may be beneficial in prostate cancer treatment.

PURPOSE The prostate specific antigen (PSA) level usually is lowered in response to initial endocrine therapy even in advanced cases of prostate cancer, but in some cases, it is not. We examined the cases in which the PSA level was not sufficiently lowered by initial endocrine therapy with maximal androgen blockade (MAB) or estrogenic drugs. MATERIALS AND METHODS The subjects were 20 patients with prostate cancer diagnosed between January 1992 and December 2005 whose PSA level was not lowered below 10 ng/ml after initial endocrine therapy with MAB or estrogenic drugs. We investigated the frequency of cases, pretreatment PSA levels, PSA nadir levels after initial endocrine therapy and throughout the therapy, PSA response to second line therapy, and the prognosis. RESULTS The PSA level was not lowered below 10 ng/ml after initial endocrine therapy with MAB or estrogenic drugs in 4.9% of the cases. Cancer-specific survival rates in all cases were extremely poor, 75.0% at 1 year and 14.7% at 3 years. Prognosis tended to be worse in patients with a higher PSA nadir level throughout the therapy and on whom second therapy was not effective, although the difference was not statistically significant. CONCLUSION The patients whose PSA levels were not lowered sufficiently by MAB or estrogenic drugs had an extremely poor prognosis. These results are useful in planning the therapy, and in explaining the status or future prospective of the disease to patients and their families.

Statins have recently been studied for their proapoptotic and antimetastatic effects. However, the exact mechanisms of their anticancer actions remain unclear. Using microarrays, we discovered up-regulation of annexin A10 (ANXA10) in PC-3 cells after simvastatin treatment. ANXA10 reportedly has antitumor effects. In this study, we evaluated the effects of simvastatin on ANXA10 signaling in androgen-independent prostate cancer cells.PC-3, LNCaP-LA (which were derived from LNCaP cells and cultured in 10% charcoal-stripped fetal bovine serum for 3 months), and DU145 human prostate cancer cell lines were used. Prostate tissues were collected from 60 patients (benign prostatic hyperplasia [BPH], n = 20; prostate cancer with a Gleason score of 7, n = 20; prostate cancer with a Gleason score of 8-10, n = 20) at the time of prostate biopsies performed. We used a nude mouse tumor xenograft model with administration of simvastatin or phosphate-buffered saline via intraperitoneal injection.Simvastatin inhibited the proliferation, migration, and invasion of PC-3, LNCaP-LA, and DU145 cells. The expression level of ANXA10 was up-regulated by simvastatin in PC-3, LNCaP-LA, and DU145 cells. Transfection with ANXA10 inhibited PC-3 and LNCaP-LA cells proliferation, migration, and invasion. Knockdown of ANXA10 by siRNA increased the proliferation of PC-3 and LNCaP-LA cells. In a nude mouse xenograft model of PC-3 cells, simvastatin induced both reduction in the tumor size and up-regulation of ANXA10 expression. In human prostate biopsy samples, ANXA10 mRNA expression was significantly lower in the prostate cancer group than in the BPH group. Next, we found that up-regulation of ANXA10 in PC-3 resulted in down-regulation of S100 calcium binding protein A4 (S100A4), which is reportedly correlated with aggressiveness and a worse prognosis for patients with different types of carcinomas. Expression of S100A4 was down-regulated by simvastatin. In PC-3 cells, knockdown of S100A4 by siRNA inhibited the proliferation, migration, and invasion of PC-3 cells.Our results suggest that statins inhibit the proliferation, migration, and invasion of androgen-independent prostate cancer cells by up-regulation of ANXA10. Additionally, it is possible that S100A4 plays a role in these effects. Statins may be beneficial in the prevention and/or treatment of prostate cancer. Prostate 77: 337-349, 2017. © 2016 Wiley Periodicals, Inc.

We developed the alarm fuse for High Voltage Direct Current (HVDC) power system. It was realized stable breaking characteristics and low transient voltage by our specific know-how for interrupting DC voltage and unique shape of fuse element.

Objectives To investigate the levels of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prostate-specific antigen (PSA) in prostate cancer patients before and after the switch from degarelix to leuprolide treatments. Methods We enrolled 40 treatment-naïve prostate cancer patients who were treated initially with degarelix and were later switched to leuprolide. The subjects were divided into three groups depending on when they were switched to leuprolide: the 3-month group (3m; switched after 84 days, n=10), the 2-month group (2m; 56 days, n=10), and the 1-month group (1m; 28 days, n=20). Patient symptoms and hormone levels were measured after switching therapy. The castration level was defined as a serum testosterone level ≤50 ng/dl. Results Thirty-nine subjects (97.5%) achieved castration levels of testosterone (11±5.8 ng/dl) 2 weeks after degarelix was first administered, and the characteristics of these patients were investigated. Testosterone levels increased and exceeded the castration level in one subject each of the 3m (142 ng/dl), 2m (72 ng/dl), and 1m groups (63 ng/dl). All subjects achieved the castration level by day 5. In contrast to testosterone levels, the LH and FSH surge on day 2 was significantly higher in the 1m group than in the other groups. The clinical symptoms were not exacerbated before or after switching in any patients. Conclusions A testosterone surge was observed in 8.3 % of the study patients; however, it was very short-lived and mild. LH and FSH levels were significantly higher 1 month after administration compared with 2 or 3 months after degarelix administration.

Object: Statins have been studied for their proapoptic and antimetastatic effects, which may make them relevant to cancer prevention or treatment. Some studies have shown a decreased risk of developing cancer in general. Concerning prostate cancer, the anticancer effect of statins is controversial. In vitro, some reports showed that statins have biological activities which inhibit PC proliferation, lowering the raft cholesterol content and inhibition of cyclin-dependent-kinase- 2 activity. However, the exact mechanisms of their anticancer action are still unclear. Statins lower cholesterol by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis. In normal cells, a decrease of intracellular cholesterol level induces an expression of low-density lipoprotein receptor (LDLR). On the other hand, it is reported that the regulation of LDLR expression is lacking in androgen-independent prostate cancer. We assessed the effect of several statins on the proliferation of prostate cancer cells, and studied the relationship between the expression of LDLR and the effect of statins. Methods: Simvastain, lovastatin, NK104, fluvastatin, pravastatin were used for our experiments. We examined the effect of statins on LNCaP and PC-3 cell proliferations by MTS assay, and evaluated the expression of LDLR after administrations of statins by Western blotting. Intracellular cholesterol levels of LNCaP and PC-3 cells were measured after administration of simvastatin. Furthermore, small interfering RNA (siRNA) were used to knock down the gene expression of LDLR. Results: In both prostate cancer cell lines, lipophilic statins inhibited cell proliferations. But pravastatin, water-soluble statin, did not significantly inhibit cell proliferations. In PC-3 cells, low dose statins (1 μM) inhibited cell proliferation. Otherwise, in LNCaP cells, only high dose statins (100 μM) inhibited cell proliferation. In LNCaP cells, the protein expression of LDLR was increased after treatment of statins. On the other hand, In PC-3 cells, statin did not regulate the expression of LDLR. In PC-3 cells, intracellular cholesterol levels were significantly decreased by simvastatin, but not in LNCaP cells. After knocking down of LDLR expression by LDLR siRNA, cell proliferation was inhibited by 10 μM of simvastatin in LNCaP cells. Conclusion: Statins inhibited proliferation of PC-3 cells and LNCaP cells after transfection of LDLR siRNA. These findings suggested that LDLR plays an important role in inhibition of prostate cancer cell proliferation by statin, and statins could be more effective in androgen-independent prostate cancer which lacks an ability to regulate an expression of LDLR. Future studies on the effect of diet and lipid-modulating drugs may uncover new approaches for the prevention and treatment of prostate cancer. Citation Format: Yosuke Furuya, Yoshitaka Sekine, Hidekazu Koike, Hiroshi Matsui, Kazuhiro Suzuki. LDL receptor plays an important role in inhibition of prostate cancer cell proliferation by statin [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B50.