OBJECTIVEThe current study aims to investigate the effect of Hemagglutinating virus of Japan envelope (HVJ-E) on induction of apoptosis and autophagy in human prostate cancer PC3 cells, and the underlying mechanisms.

METHODSPC3 cells were treated with HVJ-E at various multiplicity of infection (MOI), and the generated reactive oxygen species (ROS), cell viability, apoptosis, and autophagy were detected, respectively. Next, the role of ROS played in the regulation of HVJ-E-induced apoptosis and autuphagy in PC3 cells were analysed. In the end, the relationship between HVJ-E-induced apoptosis and autuophagy was investigated by using rapamycin and chloroquine.

RESULTSFlow cytometry assay revealed that HVJ-E treatment induced dose-dependent apoptosis and that the JNK and p38 MAPK signaling pathways were involved in HVJ-E-induced apoptosis in PC3 cells. In addition, HVJ-E was able to induce autophagy in PC3 cells via the class III PI3K/beclin-1 pathway. The data also implyed that HVJ-E-triggered autophagy and apoptosis were ROS dependent. When ROS was blocked with N-acetylcysteine (NAC), HVJ-E-induced LC3-II conversion and apoptosis were reversed. Interestingly, HVJ-E-induced apoptosis was significantly increased by an inducer of autophagy, rapamycin pretreatment, both in vitro and in vivo.

CONCLUSIONHVJ-E exerts anticancer effects via autophagic cell death in prostate cancer cells.

Apoptosis ; physiology ; Autophagy ; physiology ; Cell Line, Tumor ; Cell Survival ; Humans ; Male ; Oncolytic Virotherapy ; Prostatic Neoplasms ; metabolism ; Reactive Oxygen Species ; metabolism ; Sendai virus ; immunology ; physiology ; Virus Inactivation

Prostate cancer is characterized by bone metastases and difficulty of objectively measuring disease burden. In this context, cell-free circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) quantitation and genomic profiling afford the ability to noninvasively and serially monitor the tumor. Recent data suggest that ctDNA and CTC quantitation are prognostic for survival. Indeed, CTC enumeration using the CellSearch^® platform is validated as a prognostic factor and warrants consideration as a stratification factor in randomized trials. Changes in quantities of CTCs using CellSearch also are prognostic and may be employed to detect a signal of activity of new agents. Molecular profiling of both CTCs and ctDNA for androgen receptor (AR) variants has been associated with outcomes in the setting of novel androgen inhibitors. Serial profiling to detect the evolution of new alterations may inform drug development and help develop precision medicine. The costs of these assays and the small quantities in which they are detectable in blood are a limitation, and novel platforms are required to address this challenge. The presence of multiple platforms to assay CTCs and ctDNA also warrants the consideration of a mechanism to allow comparison of data across platforms. Further validation and the continued development and standardization of these promising modalities will facilitate their adoption in the clinic.
Biomarkers, Tumor/blood* ; DNA, Neoplasm/blood* ; Humans ; Male ; Neoplastic Cells, Circulating/immunology* ; Prognosis ; Prostatic Neoplasms/pathology* ; Transcriptome

OBJECTIVETo investigate the changes of CD4 + CD25 + Foxp3 + regulatory T cells in the peripheral blood mononuclear cells (PBMC) and their association with insulin resistance in different stages of prostate cancer (PCa).

METHODSUsing flow cytometry, we counted the CD4+ CD25 + Foxp3 + regulatory T cells in the PBMCs of 62 PCa patients (5 cases of TNM stage I, 16 cases of stage II, 21 cases of stage III, and 20 cases of stage IV) and 42 normal healthy controls, and calculated their proportion in the CD4+ T-lymphocytes. We determined the levels of fast blood glucose (FBG) and fast insulin (FINS) for the insulin resistance index (HOMA-IR), obtained the serum IGF-1 level by ELISA, and analyzed the relationship of the count and proportion of CD4+ CD25+ Foxp3+ regulatory T cells with insulin resistance by comparison between the PCa patients and normal healthy controls.

RESULTSCompared with the control group, the PCa patients showed significantly increased HOMA-IR (3.68 ± 1.42 vs 6.68 ± 1.66), decreased level of serum IGF-1 ([164.56 ± 30.58] vs [96.39 ± 21.21] ng/ml), and elevated count ([1.99 ± 0.78 ] x 10(7) vs [3.55 ± 0.29] x 10(7)) and proportion ([5.33 ± 0.65] vs [13.88 ± 0.96]%) of CD4 + CD25 + Foxp3 regulatory T cells in the PBMCs. The TNM stage was correlated positively with the count and percentage of CD4 + CD25+ Foxp3 + regulatory T cells and HOMA-IR, but negatively with the level of serum IGF-1. Meanwhile, the count and percentage of CD4 + CD25 + Foxp3 + regulatory T cells were found to have a positive correlation with HOMA-IR (r = 0.722 and 0.689, P < 0.01) but a negative correlation with the level of serum IGF-1 (r = -0.747 and -0.896, P < 0.01).

CONCLUSIONThe count and proportion of CD4+ CD25 + Foxp3 + regulatory T cells in the peripheral blood and insulin resistance increase with the elevated stage of PCa. CD4 + CD25 + Foxp3 + regulatory T cells may be involved in the occurrence and progression of PCa by regulating insulin resistance.

Aged ; CD8-Positive T-Lymphocytes ; Case-Control Studies ; Disease Progression ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Humans ; Hyperinsulinism ; Insulin ; blood ; Insulin Resistance ; Insulin-Like Growth Factor I ; metabolism ; Leukocytes, Mononuclear ; Lymphocyte Count ; Male ; Prostatic Neoplasms ; blood ; immunology ; pathology ; T-Lymphocytes, Regulatory

Serum prostate-specific antigen (PSA) is composed of the PSA precursor protein (proPSA) in the absence of the leader peptide induced by human kallikrein 2 (hK2). There are many forms of PSA in the blood, including free PSA and bound PSA. Serum proPSA, as a free PSA, has many isoforms, among which, [-2]proPSA (p2PSA) cannot be activated by hK2 and therefore exists stably in the blood. Serum p2PSA is a homologous isomer of PSA. Serum prostate health index and % p2PSA, as the derivative indexes of p2PSA and molecular markers associated with the development and progression of prostate cancer, can reduce serum PSA test-induced excessive diagnosis and treatment of the malignancy and improve the accuracy of its prediction. This review summarizes recent progress in the studies of serum p2PSA and its derivative indexes in prostate cancer.
Humans ; Male ; Prostate-Specific Antigen ; blood ; Prostatic Neoplasms ; blood ; immunology ; Protein Isoforms ; blood

Heterophilic antibodies are human immunoglobulins directed against various animal antigens. They can produce false-positive results in the analysis of different tumor markers, including prostate-specific antigen. This interference can lead to misdiagnosis, unnecessary tests, and overtreatment in some cases. We present herein the case of a 52-year-old man with repeated spurious elevation of prostate-specific antigen, reaching levels of 108.7 ng/mL, that were suspected to be caused by heterophilic antibodies. The interference was solved by changing the analysis technique. Real values of prostate-specific antigen were less than 1 ng/mL.
Antibodies, Heterophile/*immunology ; False Positive Reactions ; Humans ; Luminescence ; Male ; Middle Aged ; Prostate-Specific Antigen/*blood ; Prostatic Neoplasms/blood/*diagnosis/immunology

OBJECTIVE: To explore the expression of perforin and granzyme-B in peripheral blood lymphocyte (PBL) in patients with prostate cancer (PCa) and the clinical significance. METHODS: The expressions of perforin and granzyme-B in PBL were detected by fluorescence quantitative reverse transcription polymerase chain reaction. The results of perforin and granzyme-B expression were compared among patients with PCa (n=60), patients with BPH (benign prostatic hyperplasia, n=40) and healthy controls (n=20). RESULTS: Th e expressions of perforin and granzyme-B in patients with PCa were significantly lower than that in patients with BPH or that in the healthy controls (P<0.05), respectively. Furthermore, in PCa patients with low pathological grade, the expressions of perforin and granzyme-B in PBL was statistically higher than that in patients with high pathological grade (P<0.05). The expressions of perforin and granzyme-B in PCa patients at high clinical stage was statistically lower than that in PCa patients at low clinical stage (P<0.05). CONCLUSION The results of this study suggest that development and progression of PCa might be associated with poor immune status of patients.
Case-Control Studies ; Granzymes ; metabolism ; Humans ; Lymphocytes ; enzymology ; Male ; Perforin ; metabolism ; Prostatic Hyperplasia ; Prostatic Neoplasms ; immunology

OBJECTIVEInactivated Sendai virus particle [hemagglutinating virus of Japan envelope (HVJ-E)] has a potential oncolytic effect due to its ability to induce apoptosis in tumor cells. However, the molecular mechanism of apoptosis induction in cancer cells mediated by HVJ-E has not been fully elucidated. This paper aims to investigate the underlying mechanism of apoptosis induction by HVJ-E in prostate cancer cells (PC3).

METHODSPC3 cells were treated with HVJ-E at various MOI, and then interferon-β (IFN-β) production, and the cell viability and apoptosis were detected by ELISA, MTT-based assay and flow cytometry, respectively. Next, the roles of Jak-Stat, MAPK and Akt pathways played in HVJ-E-induced apoptosis in PC3 cells were analyzed by immunoblot assay. To further evaluate the cytotoxic effect of HVJ-E on PC3 cells, HVJ-E was intratumorally injected into prostate cancers on BALB/c-nude mice, and the tumor volume was monitored for 36 days.

RESULTSHVJ-E induced IFN-β production and activated Jak-Stat signaling pathway, which resulted in the activation of caspase-8, caspase-3, and PARP in PC3 prostate cancer cells post HVJ-E treatment. Furthermore, we observed for the first time that p38 and Jnk MAPKs in PC3 cells contributed to HVJ-E-induced apoptosis. In addition, intratumoral HVJ-E treatment displayed a direct inhibitory effect in an in vivo BALB/c nude mouse prostate cancer model.

CONCLUSIONOur findings have provided novel insights into the underlying mechanisms by which HVJ-E induces apoptosis in tumor cells.

Animals ; Apoptosis ; Cancer Vaccines ; immunology ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Oncolytic Virotherapy ; Prostatic Neoplasms ; Sendai virus ; immunology ; physiology ; Vaccines, Inactivated ; immunology

OBJECTIVETo evaluate the efficacy and safety of dendritic cell (DC)-based vaccines in the treatment of prostate cancer, and investigate the factors that influence the clinical benefit rate (CBR) of the vaccines.

METHODSBased on pre-determined search criteria, we searched the Medline database for randomized controlled trials on DC-based vaccines immunotherapy of prostate cancer. We systematically analyzed the identified studies using RevMan 5.0 and SPSS 17.0 softwares.

RESULTSTen randomized controlled trials involving 179 prostate cancer patients were identified and subjected to meta-analysis. The CBR of the DC vaccines for prostate cancer was 54.2% , and the objective response rate was 7.7%. Most adverse effects were local reactions at the injection site, fever and flu-like symptoms. The prostate cancer patients achieved cellular immune response (OR = 31.12, 95% CI = 5.52-175.6, P < 0.01) and reduction of log PSA slope (OR = 4.38, 95% CI = 1.17-16.35, P = 0.03) after administration of DC vaccines, which was positively correlated with CBR. The dose of DC vaccines had a significant correlation with CBR (OR = 5.98, 95% CI = 1.45-24.62, P = 0.01), but not the age of the patients (P = 0.53). Besides, density-enriched DCs achieved a higher CBR, while the route of administration had no effect on CBR.

CONCLUSIONDC-based vaccines are effective, safe and well-tolerated in the treatment of prostate cancer. DC-mediated cellular immune response has a significant effect on CBR and can be used as an important index for the assessment of vaccines. More multi-centered randomized controlled trials of higher quality and larger sample size are needed to provide more valid evidence.

Cancer Vaccines ; adverse effects ; immunology ; therapeutic use ; Dendritic Cells ; immunology ; Humans ; Male ; Prostatic Neoplasms ; prevention & control ; Randomized Controlled Trials as Topic

OBJECTIVETo investigate the expression of heat shock protein 90 (HSP90) on the cell surface of highly invasive human prostate cancer cells PC3 and its possible molecular mechanisms of its effect on cell invasion through analyzing FAK/Src signaling pathway.

METHODSThe expression of cell surface HSP90 on PC3 cells was studied by immunofluorescence staining and surface biotinylation assay respectively. A specific HSP90 antibody was used to inhibit the cell surface HSP90. In vitro cell invasion was assessed by modified Boyden chambers. Phosphorylated FAK on tyr 397, 576, 577 and 925, and phosphorylated c-Src on tyr 416 were examined by Western blot assay. The association between FAK and c-Src was analyzed by immunoprecipitation. The effects of FAK knockdown by siRNA or Src kinases inhibitor PP2, with or without anti-HSP90 antibody, on PC3 cell invasion were also evaluated.

RESULTSA pool of HSP90 was detected on the cell surface of PC3 cells. A specific HSP90 antibody significantly retarded tumor cell invasion. Concomitant with this finding, targeting cell surface HSP90 significantly inhibited the phosphorylations of FAK and c-Src, and also the interactions between FAK and c-Src. FAK knockdown or PP2 dramatically suppressed cell invasion, however, anti-HSP90 antibody didn't further inhibit cell invasion.

CONCLUSIONSCell surface HSP90 promotes human prostate cancer cell invasion through a FAK/c-Src signaling, with may be a novel therapeutic target against metastatic tumors.

Antibodies ; pharmacology ; Cell Line, Tumor ; Cell Membrane ; metabolism ; Focal Adhesion Protein-Tyrosine Kinases ; genetics ; metabolism ; Gene Knockdown Techniques ; HSP90 Heat-Shock Proteins ; immunology ; metabolism ; Humans ; Male ; Neoplasm Invasiveness ; Phosphorylation ; Prostatic Neoplasms ; metabolism ; pathology ; Pyrimidines ; pharmacology ; RNA, Small Interfering ; genetics ; Signal Transduction ; Transfection ; src-Family Kinases ; antagonists & inhibitors ; metabolism

Metastasis represents by far the most feared complication of prostate carcinoma and is the main cause of death for patients. The skeleton is frequently targeted by disseminated cancer cells and represents the sole site of spread in more than 80% of prostate cancer cases. Compatibility between select malignant phenotypes and the microenvironment of colonized tissues is broadly recognized as the culprit for the organ-tropism of cancer cells. Here, we review our recent studies showing that the expression of platelet-derived growth factor receptor alpha (PDGFRα) supports the survival and growth of prostate cancer cells in the skeleton and that the soluble fraction of bone marrow activates PDGFRα in a ligand-independent fashion. Finally, we offer pre-clinical evidence that this receptor is a viable target for therapy.
Animals ; Antibodies, Monoclonal ; therapeutic use ; Bone Marrow ; enzymology ; pathology ; Bone Neoplasms ; prevention & control ; secondary ; Enzyme Activation ; Humans ; Male ; Prostatic Neoplasms ; drug therapy ; enzymology ; pathology ; Receptor, Platelet-Derived Growth Factor alpha ; antagonists & inhibitors ; genetics ; immunology ; metabolism ; Signal Transduction ; Transcriptional Activation