Prostate Cell Proliferation Research Articles

Changes in the expression and functional activities of Myosin II isoforms in human hyperplastic prostate

Benign prostatic hyperplasia (BPH) is a common disease among aging males with the etiology remaining unclear. We recently found myosin II was abundantly expressed in rat and cultured human prostate cells with permissive roles in the dynamic and static components. This study aimed to explore the expression and functional activities of myosin II isoforms including smooth muscle myosin II (SMM II) and non-muscle myosin (NMM II) in the hyperplastic prostate. Human prostate cell lines and tissues from normal human and BPH patients were used. H&E, Masson's trichrome, immunohistochemical staining, in vitro organ bath, RT-PCR and Western-blotting were performed. We further created cell models with NMM II isoforms silenced and proliferation, cycle, and apoptosis of prostate cells were determined by CCK-8 assay and flow cytometry. Hyperplastic prostate SM expressed more SM1 and LC17b isoforms compared to their alternatively spliced counterparts, favoring a slower more tonic-type contraction and greater force generation. For BPH group, blebbistatin (BLEB, a selective myosin II inhibitor), exhibited a stronger effect on relaxing phenylephrine (PE) pre-contracted prostate strips and inhibiting PE induced contraction. Additionally, NMMHC-A and NMMHC-B were upregulated in hyperplastic prostate with no change in NMMHC-C. Knockdown of NMMHC-A or NMMHC-B inhibited prostate cell proliferation and induced apoptosis, with no changes in cell cycle. Our novel data demonstrates that expression and functional activities of myosin II isoforms are altered in human hyperplastic prostate, suggesting a new pathological mechanism for BPH. Thus, the myosin II system may provide potential new therapeutic targets for BPH/lower urinary tract symptoms (LUTS).

Proximity-dependent Mapping of the Androgen Receptor Identifies Kruppel-like Factor 4 as a Functional Partner

Prostate cancer (PCa) is the most frequently diagnosed cancer in men and the third cause of cancer mortality. PCa initiation and growth are driven by the androgen receptor (AR). The AR is activated by androgens such as testosterone and controls prostatic cell proliferation and survival. Here, we report an AR signaling network generated using BioID proximity labeling proteomics in androgen-dependent LAPC4 cells. We identified 31 AR-associated proteins in nonstimulated cells. Strikingly, the AR signaling network increased to 182 and 200 proteins, upon 24 h or 72 h of androgenic stimulation, respectively, for a total of 267 nonredundant AR-associated candidates. Among the latter group, we identified 213 proteins that were not previously reported in databases. Many of these new AR-associated proteins are involved in DNA metabolism, RNA processing, and RNA polymerase II transcription. Moreover, we identified 44 transcription factors, including the Kru¨ppel-like factor 4 (KLF4), which were found interacting in androgen-stimulated cells. Interestingly, KLF4 repressed the well-characterized AR-dependent transcription of the KLK3 (PSA) gene; AR and KLF4 also colocalized genome-wide. Taken together, our data report an expanded high-confidence proximity network for AR, which will be instrumental to further dissect the molecular mechanisms underlying androgen signaling in PCa cells.

MiR-181c inhibits prostatic epithelial cell proliferation caused by chronic non-bacterial prostatitis through downregulating COX-2

Background: Chronic non-bacterial prostatitis (CNP) is a widespread disease of the male reproductive system. MiR-181c can be expressed in prostate tissue, but it has not been reported in CNP. This study aims to investigate the role of miR-181c in CNP and its mechanism of action on CNP, providing new ideas for the treatment and diagnosis of CNP. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were applied to determine miR-181c expression in clinical CP patients, CNP rats, and LPS-induced human prostaglandin epithelial cell RWPE-1. Then, luciferase reporter assay was performed to verify the targeting relation between miR-181c and COX-2. Through cell transfection experiments, the effect of mi-181c on the expression of COX2 and PGE2 was studied, and the effect of miR-181c/COX-2 on the proliferation of prostate epithelial cells was also explored. Results: qRT-PCR and Western blotting analysis revealed that miR-181c was low expressed in prostate tissue of CP patients and CNP rats and human prostaglandin epithelial cell RWPE-1. The luciferase reporter assay confirmed the targeting relation between miR-181c and COX-2. And miR-181c overexpression reduced the expression of COX-2 and PGE2 and suppressed the proliferation of prostate epithelial cells. COX-2 up-regulation reversed these effects caused by overexpression of miR-181c. Conclusions: miR-181c inhibited the proliferation of prostate epithelial cells through negatively regulating COX-2 to alleviate chronic non-bacterial prostatitis. Keywords: Chronic non-bacterial prostatitis, miR-181c, COX-2, prostatic epithelial cell, proliferation

Cordyceps militaris Fruit Body Extract Decreases Testosterone Catabolism and Testosterone-Stimulated Prostate Hypertrophy.

The androgens testosterone and dihydrotestosterone (DHT) are essential for a variety of systemic functions in mature males. Alteration of these hormones results in late-onset hypogonadism (LOH) and benign prostate hyperplasia (BPH). The fruit bodies of fungi of the genus Cordyceps have been regarded as folk medicine or health food with tonic and antifatigue effects. The extract from the fruit body of Cordyceps militaris parasitizing Samia cynthia ricini (CM) was evaluated as a novel-candidate natural product for ameliorating male andropause symptoms. To explore the effects of CM on LOH and BPH, CM was applied to rat models and cultured testicular cells and prostate cells. The concentrations of androgens in the serum and culture media were determined by ELISA. Expression of steroidogenic enzymes and androgen-related genes was evaluated by qPCR, and prostatic cell proliferation was assessed with the cell-viability assay. CM maintained the serum levels of testosterone and DHT, but inhibited testosterone-induced prostate hypertrophy. CM also increased the secretion of testosterone and DHT by primary testicular cells, with no changes in the mRNA expression of steroidogenic enzymes, but decreased the growth of prostatic cell lines. Our data suggest that CM could improve both LOH and BPH in males.

Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia.

Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders.

The targeted inhibition of prostate cancer by iron-based nanoparticles based on bioinformatics.

Prostate cancer is an epithelial malignant tumor of the prostate, and it is one of the malignant tumors with a high incidence of urogenital system in men. The local treatment of prostate cancer is mainly radical resection and radical radiotherapy, but they are not applicable to advanced prostate cancer. Systemic therapy mainly includes targeted therapy and immunotherapy which could cause many complications, and will affect the prognosis and quality of life of patients. It is urgent to find new treatments for prostate cancer. Bioinformatics offers hope for us to find reliable therapeutic targets. Bioinformatics can use the tumor informations in database and analyze them to screen out the best differentially expressed genes. Using the selected differentially expressed genes as targets, a gene interference plasmid was designed, and the constructed plasmid was used for targeted gene therapy. There are some problems about gene therapy that need to be solved, such as how to transfer genes to target cells is also an important challenge. Due to their large molecular weight and hydrophilic nature, they cannot enter cells through passive diffusion mechanisms. Here we synthesized a DNA carrier used surface modified iron based nanoparticles, and used it to load plasmid including ShRNA which can inhibit the expression of oncogene SLC4A4 selected by bioinformatics’ method. After that we use this iron based nanoparticles/plasmid DNA nanocomposite to treat prostate cancer cells in vitro and in vivo. The target gene SLC4A4 we had selected using bioinformatics had a strong effect on the proliferation of prostate cells; Our nanocomposite could inhibit the expression of SLC4A4 effectively, it had strong inhibitory effects on prostate cancer cells both in vivo and in vitro, and can be used as a potential method for prostate cancer treatment.

LDL, HDL and endocrine-related cancer: From pathogenic mechanisms to therapies.

Cholesterol is essential for a variety of functions in endocrine-related cells, including hormone and steroid production. We have reviewed the progress to date in research on the role of the main cholesterol-containing lipoproteins; low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and their impact on intracellular cholesterol homeostasis and carcinogenic pathways in endocrine-related cancers. Neither LDL-cholesterol (LDL-C) nor HDL-cholesterol (HDL-C) was consistently associated with endocrine-related cancer risk. However, preclinical studies showed that LDL receptor plays a critical role in endocrine-related tumor cells, mainly by enhancing circulating LDL-C uptake and modulating tumorigenic signaling pathways. Although scavenger receptor type BI-mediated uptake of HDL could enhance cell proliferation in breast, prostate, and ovarian cancer, these effects may be counteracted by the antioxidant and anti-inflammatory properties of HDL. Moreover, 27-hydroxycholesterol a metabolite of cholesterol promotes tumorigenic processes in breast and epithelial thyroid cancer. Furthermore, statins have been reported to reduce the incidence of breast, prostate, pancreatic, and ovarian cancer in large clinical trials, in part because of their ability to lower cholesterol synthesis. Overall, cholesterol homeostasis deregulation in endocrine-related cancers offers new therapeutic opportunities, but more mechanistic studies are needed to translate the preclinical findings into clinical therapies.

ETV4 promotes late development of prostatic intraepithelial neoplasia and cell proliferation through direct and p53-mediated downregulation of p21

BackgroundETV4 is one of the ETS proteins overexpressed in prostate cancer (PC) as a result of recurrent chromosomal translocations. In human prostate cell lines, ETV4 promotes migration, invasion, and proliferation; however, its role in PC has been unclear. In this study, we have explored the effects of ETV4 expression in the prostate in a novel transgenic mouse model.MethodsWe have created a mouse model with prostate-specific expression of ETV4 (ETV4 mice). By histochemical and molecular analysis, we have investigated in these engineered mice the expression of p21, p27, and p53. The implications of our in vivo findings have been further investigated in human cells lines by chromatin-immunoprecipitation (ChIP) and luciferase assays.ResultsETV4 mice, from two independent transgenic lines, have increased cell proliferation in their prostate and two-thirds of them, by the age of 10 months, developed mouse prostatic intraepithelial neoplasia (mPIN). In these mice, cdkn1a and its p21 protein product were reduced compared to controls; p27 protein was also reduced. By ChIP assay in human prostate cell lines, we show that ETV4 binds to a specific site (-704/-696 bp upstream of the transcription start) in the CDKN1A promoter that was proven, by luciferase assay, to be functionally competent. ETV4 further controls CDKN1A expression by downregulating p53 protein: this reduction of p53 was confirmed in vivo in ETV4 mice.ConclusionsETV4 overexpression results in the development of mPIN but not in progression to cancer. ETV4 increases prostate cell proliferation through multiple mechanisms, including downregulation of CDKN1A and its p21 protein product: this in turn is mediated through direct binding of ETV4 to the CDKN1A promoter and through the ETV4-mediated decrease of p53. This multi-faceted role of ETV4 in prostate cancer makes it a potential target for novel therapeutic approaches that could be explored in this ETV4 transgenic model.

Strength Training Modulates Prostate of Wistar Rats Submitted to High-Fat Diet.

Our aim is to evaluate the effects of high-fat diet and strength training on ventral prostate health through investigations of rat prostate histology, endocrine modulation, and the expression of proliferative and apoptotic marker, including androgen receptors (AR), glucocorticoid receptors (GR), B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (BAX), Fas cell surface death receptor (Fas/CD95/Apo-1), and Nuclear Factor Kappa-B (NF-κB). Eighty Wistar rats were into one of four subgroups: control (CT), strength training (ST), high-fat diet consumption (HF), and high-fat diet consumption with strength training (HFT). Animals then underwent strength training and/or high-fat diet consumption for 8 or 12weeks, after which animals were euthanized and markers of prostatic health were evaluated histologically and through immunolabeling. Our results indicate that physical strength training reduced the expression of the prostate cell proliferation marker Bcl-2 while increasing expression of the pro-apoptotic marker BAX, as well as increasing expression of AR and GR relevant in the Bcl-2 pathway. We conclude that a high-fat diet can alter hormone receptor levels and cell-cycle protein expression, thereby modifying prostatic homeostasis, and that strength training was able to reduce prostate damage induced by high-fat diet consumption.

Inhibitory Effect of Artemisinin on Testosterone Propionate Induced Benign Prostatic Hyperplasia.

Benign prostate hyperplasia [BPH] is an abnormal growth of prostate observed commonly in elderly males. Artemisinin has been reported to reduce the levels of testosterone. This study is designed to evaluate the efficacy of Artemisinin on testosterone propionate [TP] induced benign prostate hyperplasia. Male Wistar albino rats [n=24] were separated into four groups of six rats each. Group I served as control and distilled water using tween 80 as an emulsifying agent was administered subcutaneously. BPH was induced by testosterone propionate 3mg/kg [Group II], S.C. daily for 28 days. Group III was BPH + Finasteride treated group (10mg/kg orally for 28 days) and BPH + Artemisinin treated group (Group IV) (50 mg/kg orally for 28 days). The study results showed significantly high levels of serum prostatic acid phosphatase (PAP), lactate dehydrogenase (LDH) and an elevation in prostate weight and prostatic index in Group II (BPH) when compared with Group I. The histopathological examination showed an increase in the epithelial proliferation of prostatic cells with involutions protruding into the lumen in BPH group when compared to the normal group. Treatment with Artemisinin (50 mg/kg) reduced the levels of PAP, LDH, prostate weight and prostatic index to a significant extent and restored the histoarchitectural features of the cells. The present study concludes that Artemisinin is efficacious in testosterone propionate induced BPH. This could be attributed, at least partly, to its anti-inflammatory property or its role in testosterone level reduction or as a Vitamin D receptor modulator.

SAT-138 Neutrophil Elastase Promotes Proliferative Signals in Prostate Cells Through EGFR and DDR1

Studies examining many different cancers have demonstrated that inflammation plays a critical role in tumor progression, in part through the release of proteases from stromal cells that function to either remodel the tumor microenvironment or to directly stimulate cancer cells to grow. One specific protease, neutrophil elastase (NE), has been shown to be a critical regulator of cancer growth in several mouse models. Accordingly, our laboratory demonstrated that NE, most likely from granulocytic myeloid-derived suppressor cells, potentially promotes prostate cancer progression in several different in-vivo and in-vitro models. To date, however, little is known regarding the mechanisms utilized by NE to promote tumor growth. It has been suggested that NE might cleave epidermal growth factor (EGF) or transforming growth factor-α from the cell surface to induce activation of EGFR/ERK signal transduction in an autocrine fashion. Alternatively, NE has been shown to enter into early endosomes to degrade insulin receptor substrate-I, ultimately resulting in phosphoinositol 3-kinase hyperactivity and subsequent tumor cell proliferation. Here we demonstrate that NE triggered proliferative signals in six prostate cell lines representing the spectrum of prostate cell differentiation, including normal prostatic epithelium, benign prostatic hypertrophy, and metastatic prostate cancer. Focusing on ERK signaling, we found that the stimulatory effect of NE on ERK phosphorylation was dose dependent and was abrogated by small interfering RNA induced EGFR knockdown, as well as by pretreatment of cells with irreversible EGFR inhibitor AG1478. Unlike EGF, however, NE-initiated EGFR phosphorylation was minimal. Thus, while EGFR appears to be critical for NE-induced ERK activation, perhaps it is not extensively activated directly by NE. Notably, discoidin domain receptor-1 (DDR1) was strongly expressed in normal prostate epithelium cells, but gradually decreased and had little expression in benign and metastatic prostate cancer cells sequentially. Nevertheless, similar to EGFR knockdown, silencing of DDR1 in all cell types inhibited NE mediated pERK upregulation, suggesting that DDR1 may also be important for NE-induced action. Together, our data suggest that NE, in concert with low level signals from the EGFR and DDR1, play an important role in promoting prostate cell proliferation both in normal and cancerous prostate epithelial cells.

SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation.

The MAP kinase ERK5 contains an N-terminal kinase domain and a unique C-terminal tail including a nuclear localization signal and a transcriptional activation domain. ERK5 is activated in response to growth factors and stresses and regulates transcription at the nucleus by either phosphorylation or interaction with transcription factors. MEK5-ERK5 pathway plays an important role regulating cancer cell proliferation and survival. Therefore, it is important to define the precise molecular mechanisms implicated in ERK5 nucleo-cytoplasmic shuttling. We previously described that the molecular chaperone Hsp90 stabilizes and anchors ERK5 at the cytosol and that ERK5 nuclear shuttling requires Hsp90 dissociation. Here, we show that MEK5 or overexpression of Cdc37—mechanisms that increase nuclear ERK5—induced ERK5 Small Ubiquitin-related Modifier (SUMO)-2 modification at residues Lys6/Lys22 in cancer cells. Furthermore, mutation of these SUMO sites abolished the ability of ERK5 to translocate to the nucleus and to promote prostatic cancer PC-3 cell proliferation. We also show that overexpression of the SUMO protease SENP2 completely abolished endogenous ERK5 nuclear localization in response to epidermal growth factor (EGF) stimulation. These results allow us to propose a more precise mechanism: in response to MEK5 activation, ERK5 SUMOylation favors the dissociation of Hsp90 from the complex, allowing ERK5 nuclear shuttling and activation of the transcription.

Oleanolic Acid Ameliorates Benign Prostatic Hyperplasia by Regulating PCNA-Dependent Cell Cycle Progression In Vivo and In Vitro.

Oleanolic acid (OA) is a natural, biologically active pentacyclic triterpenoid found in Cornus officinalis. Although C. officinalis and OA have antiproliferative actions, the effects and mechanisms of OA in benign prostatic hyperplasia (BPH) are unclear. We examined the effect of OA in an animal model of testosterone-induced BPH. Male rats were injected with testosterone propionate with or without OA. The inhibitory effect of OA on BPH-1 cells was determined in vitro. Rats with BPH exhibited outstanding BPH symptoms, including prostatic enlargement, upregulated dihydrotestosterone and 5α-reductase 2 levels, and histological changes. Compared with the BPH group, the OA group showed fewer pathological alterations and regular androgen events. OA inhibited prostate cell proliferation by downregulating the expression of proliferating cell nuclear antigen (PCNA) and cell cycle markers in BPH-induced animals. This indicated that OA has superior therapeutic effect in the BPH animal model than finasteride. In vitro studies demonstrated upregulation of PCNA and cell cycle proteins, whereas OA clearly reduced this upregulation. Thus, OA may inhibit the development of BPH by targeting cell cycle progression markers. These suggest that OA is a potential agent for BPH treatment.

Post-SELEX Optimization and Characterization of a Prostate Cancer Cell-Specific Aptamer for Diagnosis.

The RNA aptamer A4 binds specifically to tumor prostate cells. A4 was modified (mA4) by adding deoxyribonucleotides to its ends to remove the reactive 2′ hydroxyl groups of RNA’s sugar at the ends of the aptamer and to make it more stable to widespread RNase contamination in laboratories. Thus, mA4 would be more suitable to use in the clinical settings of prostate cancer (PCa). We aimed to characterize this optimized oligonucleotide to verify its potential as a diagnostic tool. The sequences and structures of A4 and mA4 were compared through in silico approaches to corroborate their similarity. Then, the degradation of mA4 was measured in appropriate media and human plasma for in vitro tests. In addition, the binding abilities of A4 to prostate cells were contrasted with those of mA4. The effects of mA4 were assessed on the viability, proliferation, and migration of human prostate cell lines RWPE-1 and PC-3 in three-dimensional (3D) cell cultures. mA4 showed configurational motifs similar to those of A4, displayed a half-life in plasma substantially higher than A4, and exhibited a comparable binding capacity to that of A4 and unaltered viability, proliferation, and migration of prostatic cells. Therefore, mA4 maintains the crucial 3D structures of A4 that would allow binding to its target, as suggested by in silico and binding analyses. mA4 may be a good PCa reporter as it does not change cellular parameters of prostate cells when incubated with it. Its additional deoxyribonucleotides make mA4 inherently more chemically stable than A4, avoiding its degradation and favoring its storage and handling for clinical applications. These characteristics support the potential of mA4 to be used in diagnostic systems for PCa.

A Role of the Heme Degradation Pathway in Shaping Prostate Inflammatory Responses and Lipid Metabolism

The molecular mechanisms of prostate inflammation are unclear. We hypothesized that heme oxygenase 1 (HMOX1; HO-1), an enzyme responsible for degradation of heme to carbon monoxide, bilirubin, and iron, is an important regulator of inflammation and epithelial responses in the prostate. Injection of non-uropathogenic Escherichia coli (MG1655 strain) or phosphate-buffered saline into the urethra of mice led to increased numbers of CD45+ leukocytes and mitotic markers (phosphorylated histone H3 and phosphorylated ERK1/2) in the prostate glands. Leukocyte infiltration was elevated in the prostates harvested from mice lacking HO-1 in myeloid compartment. Conversely, exogenous carbon monoxide (250 ppm) increased IL-1β levels and suppressed cell proliferation in the prostates. Carbon monoxide did not affect the number of infiltrating CD45+ cells in the prostates of E. coli- or phosphate-buffered saline-treated mice. Interestingly, immunomodulatory effects of HO-1 and/or carbon monoxide correlated with early induction of the long-chain acyl-CoA synthetase 1 (ACSL1). ACSL1 levels were elevated in response to E. coli treatment, and macrophage-expressed ACSL1 was in part required for controlling of IL-1β expression and prostate cancer cell colony growth in soft agar. These results suggest that HO-1 and/or carbon monoxide might play a distinctive role in modulating prostate inflammation, cell proliferation, and IL-1β levels in part via an ACSL1-mediated pathway.

Effects of Artemisia judaica essential oil and ethanolic extract on experimentally-induced benign prostatic hyperplasia

Background: Recent studies have shown that the essential oil (EO) and the ethanolic extract (EE) from Artemisia judaica L., a Jordanian medicinal plant, exhibit a potent anti-angiogenic and anti-inflammatory activities. Angiogenesis and inflammation processes are known to play a role in benign prostatic hyperplasia (BPH), a disease associated with aging in men. Objectives: The present study aimed to address the effects of EO and EE on experimentally-induced BPH in rats. Materials and Methods: Four experimental groups were assigned with six rats in each group, including the corn oil vehicle as a control. The three other groups were induced to develop BPH by testosterone injection. The BPH rats were randomized into the BPH-untreated group, BPH-EO treated group (200 mg/kg/subcutaneously) and BPH-EE treated group (500 mg/kg/orally). Results: The prostate weight/body ratio and epithelial thickness showed a significant reduction in the EO and EE treated groups compared to the BPH untreated. In addition, mRNA expression levels of the proliferating marker (proliferating cell nuclear antigen), the angiogenesis marker (vascular endothelial growth factor-A) and interleukin-6; an inflammatory cytokine, were significantly down-regulated in the BPH groups that were treated with EE or EO. Conclusion: Our results indicated that in experimentally-induced BPH, EO and EE from A. judaica ameliorate BPH development by inhibiting prostatic cell proliferation, angiogenesis, and inflammation.

Standardized Seed Extract of Quisqualis indica (HU-033) Attenuates Testosterone Propionate-Induced Benign Prostatic Hyperplasia via α1-Adrenergic Receptors and Androgen/Estrogen Signaling.

Benign prostatic hyperplasia (BPH) is an age-related disease characterized by prostatic enlargement and is the most common urologic symptoms in elderly men 60 years of age and older. Previously, we documented that 70% ethanol (EtOH) seed extract of Quisqualis indica (QI) attenuates pathological condition of testosterone propionate (TP)-induced BPH rat model via modulation of proliferation and apoptosis of prostate cells. Based on this potential of QI, we produced standardized seed extract of QI (HU-033) in order to prove further mechanisms. In this study, we aimed to suggest further mechanisms underlying the relationship between BPH and HU-033. Through not only cellular and nuclear receptor functional assays, but TP-mediated BPH rat model treated with HU-033, we demonstrated that HU-033 exerted antagonist effect on α1A- and α1D-adrenergic receptors in vitro and inhibitory effect on protein expression of androgen receptor and estrogen receptor alpha in vivo. Taken together, these results suggest that HU-033 is a novel candidate for the management of BPH.

Antioxidation and Antiapoptosis Characteristics of Heme Oxygenase-1 Enhance Tumorigenesis of Human Prostate Carcinoma Cells

Heme oxygenase-1 (HO-1) has antiinflammatory and antioxidant properties and is deemed as a tissue protector. However, effects of HO-1 in prostate cancer remain in controversy. We evaluated the role of HO-1 in prostate carcinoma in vitro and in vivo.Overexpression of HO-1 did not affect prostate cell proliferation in the normal condition but enhanced cell proliferation under serum starvation. HO-1 overexpression enhanced cell invasion of PC-3 cells through epithelial–mesenchymal transition (EMT) induction, which was supported by increased Slug, N-cadherin, and vimentin expressions. In the xenograft animal study, HO-1 overexpression enhanced PC-3 cell tumor growth in vivo. HO-1 attenuated reactive oxygen species induced by H2O2 or pyocyanin treatment in PC-3 and DU145 cells. HO-1 further reduced PC-3 and DU145 cell apoptosis induced by H2O2 or serum starvation. Our results suggested that HO-1 was able to increase prostate carcinoma cell invasion in vitro and tumor growth in vivo. The EMT induction and antioxidant and antiapoptotic effects of HO-1 in the prostate carcinoma cells may be responsible for these findings.

The α1-adrenoceptor-mediated human hyperplastic prostate cells proliferation is impaired by EGF receptor inhibition

Benign prostatic hyperplasia (BPH) is an aging-related and progressive disease linked to an up-regulation of α1-adrenoceptors. The participation of EGF receptors (EGFR) in the GPCRs’ signalosome has been described but so far data about the contribution of these receptors to prostatic stromal hyperplasia are scanty. We isolated and cultured vimentin-positive prostate stromal cells obtained from BPH patients. According to intracellular Ca2+ measurements, cell proliferation and Western blotting assays, these cultured hyperplastic stromal cells express functional α1-adrenoceptors and EGFR, and proliferate in response to the α1-adrenoceptor agonist phenylephrine. Interestingly, in these cells the inhibition of EGFR signaling with GM6001, CRM197, AG1478 or PD98059 was associated with full blockage of α1-adrenoceptor-mediated cell proliferation, while cell treatment with each inhibitor alone did not alter basal cell growth. Moreover, the co-incubation of AG1478 (EGFR inhibitor) with α1A/α1D-adrenoceptor antagonists showed no additive inhibitory effect. These findings highlight a putative role of EGFR signaling to α1-adrenoceptor-mediated human prostate hyperplasia, suggesting that the inhibition of this transactivation cascade could be useful to reduce BPH progression.

Expression of KIF18A Is Associated with Increased Tumor Stage and Cell Proliferation in Prostate Cancer.

BackgroundThe role of KIF18A in tumorigenesis and tumor development has been well studied in several cancers, but not in prostate cancer. In this study, we investigated the potential prognostic utility of KIF18A and its role in prostate cancer progression.Material/MethodsWe collected prostate cancer and paracancerous tissue samples from the same patient. Immunohistochemical staining was performed to investigate the KIF18A expression levels in the clinical sample. The Cancer Genome Atlas (TCGA) database was analyzed via a bioinformatics approach to gain insight into the relationship between KIF18A expression and prognosis. We examined the effect of KIF18A knockdown on PC-3 cell proliferation via colony formation and MTT assays. Flow cytometry was used to assess the effect of KIF18A knockdown on PC-3 cell apoptosis. Transwell invasion assay was performed to assess whether KIF18A affects the invasion ability of PC-3 cells.ResultsThe KIF18A protein level was higher in PCa tissue than in paracancerous tissue. The In addition, upregulated KIF18A suggested a poor tumor stage and prognosis for prostate cancer patients. Our in vitro experiments demonstrated that KIF18A knockdown in PC-3 cells significantly inhibited proliferation and metastasis.ConclusionsHigh KIF18A expression in prostate cancer patients predicts a poor prognosis. KIF18A knockdown inhibits prostate cell proliferation and metastasis. Therefore, this study confirms the usefulness of KIF18A as an oncological prognostic indicator and a potential therapeutic target for prostate cancer.