Based on the focal adhesion kinase(FAK)/steroid receptor coactivator(Src)/extracellular regulated protein kinase(ERK) pathway, this study explored the effects of Xihuang Pills on angiogenesis, invasion, and metastasis in prostate cancer. Liquid chromatography-tandem mass spectrometry(LC-MS/MS) was used to analyze and identify the active ingredients of Xihuang Pills. Bioinformatics techniques, including R language and Perl programs, were employed to analyze the interactions between prostate cancer-related targets and the potential targets of Xihuang Pills. A subcutaneous transplantation tumor model of prostate cancer was established in nude mice using PC3 cells to verify the efficacy and molecular mechanisms of Xihuang Pills. In vitro cellular experiments, including cell proliferation assays(CCK-8), Transwell assays, scratch assays, real-time quantitative reverse transcription PCR, and Western blot, were used to detect the effects of Xihuang Pills on the proliferation, invasion, and migration of prostate cancer cells, as well as on FAK/Src/ERK pathway-related targets. LC-MS/MS identified 99 active ingredients in Xihuang Pills, including gallic acid, gentisic acid, artemisinin, corilagin, phenylbutazone-glucoside, thujic acid, and arecoic acid B. Network pharmacological analysis of the active ingredients in Xihuang Pills revealed that the FAK/Src/ERK signaling pathway was a key pathway in its anti-prostate cancer effects. In vivo and in vitro experiments confirmed that Xihuang Pills significantly inhibited the proliferation, invasion, and migration of PC3 and LNCaP cells, suppressed the growth of PC3 subcutaneous tumors, and reduced the protein expression levels related to the FAK/Src/ERK signaling pathway. In conclusion, the inhibition of angiogenesis, invasion, and metastasis by regulating the FAK/Src/ERK pathway is one of the mechanisms by which Xihuang Pills exert anti-prostate cancer effects.
Humans ; Male ; Prostatic Neoplasms/enzymology* ; Drugs, Chinese Herbal/chemistry* ; Animals ; Mice ; Cell Proliferation/drug effects* ; Mice, Nude ; Cell Movement/drug effects* ; Cell Line, Tumor ; src-Family Kinases/genetics* ; Neovascularization, Pathologic/metabolism* ; Neoplasm Metastasis ; Neoplasm Invasiveness ; Focal Adhesion Kinase 1/genetics* ; Extracellular Signal-Regulated MAP Kinases/genetics* ; MAP Kinase Signaling System/drug effects* ; Focal Adhesion Protein-Tyrosine Kinases/genetics* ; Signal Transduction/drug effects* ; Angiogenesis

Objective: To investigate the expressions of extracellular signal-regulated kinase (ERK) and p-ERK in benign and malignant prostate tissues, and whether it can be used as a marker for the prognosis of advanced prostate cancer (PCa). METHODS: Using immunohistochemical Envision, we detected the expressions of ERK1/2 and p-ERK1/2 in 20 cases of benign prostatic hyperplasia (BPH) and 40 cases of advanced PCa and analyzed their correlation with PCa metastasis, Gleason score, PSA level, and prognosis. RESULTS: The expression of ERK1/2 was remarkably higher in the advanced PCa than in the BPH cases (82.5% vs 55%, P<0.05), which was not associated with cancer metastasis, Gleason score, PSA level, or survival time of the patients with advanced PCa, and so was that of p-ERK1/2 (75.0% vs 35%, P<0.05), which was not associated with the Gleason score or PSA level of the PCa patients, either. The expression rates of p-ERK in the metastasis, non-metastasis, survival >5 yr, and survival ≤ 5 yr groups were 61.9%, 89.5%, 57.9%, and 90.5%, respectively, with statistically significant differences among these groups (P<0.05). CONCLUSIONS ERK1/2 and p-ERK1/2 proteins are highly expressed in advanced PCa and p-ERK1/2 is associated with the metastasis and prognosis of advanced PCa.
Biomarkers, Tumor ; metabolism ; Extracellular Signal-Regulated MAP Kinases ; metabolism ; Humans ; Male ; Mitogen-Activated Protein Kinase 1 ; metabolism ; Mitogen-Activated Protein Kinase 3 ; metabolism ; Neoplasm Grading ; Neoplasm Metastasis ; Prognosis ; Prostate ; enzymology ; Prostate-Specific Antigen ; metabolism ; Prostatic Hyperplasia ; enzymology ; pathology ; Prostatic Neoplasms ; enzymology ; mortality ; pathology

Objective: To investigate the expressions of JNK and p-JNK in advanced prostate cancer (PCa) and benign prostatic hyperplasia (BPH) and their implications. METHODS: Using immunohistochemistry, we detected the expressions of JNK and p-JNK proteins in 40 cases of paraffin wax-embedded PCa and 21 cases of BPH tissues and analyzed their relationships with advanced PCa and BPH as well as with the pathologic features of advanced PCa. RESULTS: Statistically significant differences were not found in the positive expression rate of the JNK protein between BPH and PCa (42.86% vs 52.50%, P>0.05), non-metastatic and metastatic PCa (53.85% vs 51.85%, P >0.05), Gleason ≤7 and Gleason >7 (58.82% vs 47.82%, P >0.05), PSA ≤20 μg/L and PSA >20 μg/L (57.14% vs 51.52%, P >0.05), or survival >5 yr and survival ≤5 yr (60.00% vs 45.00%, P >0.05), nor in the expression level of p-JNK between BPH and PCa (33.33% vs 35.00%, P >0.05), non-metastatic and metastatic PCa (30.77% vs 37.03%, P >0.05), Gleason ≤7 and Gleason >7 (35.29% vs 34.78%, P >0.05), or PSA ≤20 μg/L and PSA >20 μg/L (43.75% vs 10.93%, P >0.05). However, the expression of p-JNK was significantly higher in the survival >5 yr than in the survival ≤5 yr group of the PCa patients (50.00% vs 20.00%, P <0.05). CONCLUSIONS PCa patients with highly expressed p-JNK have a longer survival time and the high positive rate of p-JNK is associated with the prognosis of PCa.
Humans ; Immunohistochemistry ; JNK Mitogen-Activated Protein Kinases ; metabolism ; Male ; Neoplasm Grading ; Neoplasm Proteins ; metabolism ; Prognosis ; Prostate-Specific Antigen ; metabolism ; Prostatic Hyperplasia ; enzymology ; mortality ; pathology ; Prostatic Neoplasms ; enzymology ; mortality ; pathology

Advanced prostate cancer, especially at the castration-resistant stage, remains incurable clinically and, therefore, urgently requires new therapeutics for the patients. PI3K is a family of critical cell signal transduction molecules and their over-activation is an important factor in cancer development and progression. It has been demonstrated that class IA PI3K p110 is drastically overexpressed in prostate cancer and involved in androgen receptor-mediated gene expression and castration-resistant progression and regarded as a potential therapeutic target for prostate cancer. Several p110-specific inhibitors have been reported recently and two of them, GSK2636771 and AZD8186, are being tested in clinical trials.
Aniline Compounds ; therapeutic use ; Chromones ; therapeutic use ; Humans ; Imidazoles ; therapeutic use ; Male ; Morpholines ; therapeutic use ; Neoplasm Proteins ; antagonists & inhibitors ; Phosphatidylinositol 3-Kinases ; metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Prostatic Neoplasms, Castration-Resistant ; drug therapy ; enzymology ; Protein Kinase Inhibitors ; therapeutic use

Glycogen synthase kinase3 (GSK3α and GSK3β) are serine/threonine protein kinases acting on numerous substrates and involved in the regulation of various cellular functions such as their proliferation, survival, glycogen metabolism, and autophagy. Accumulating evidence indicates that the expression of GSK3α is increased mainly in androgendependent while that of GSK3β in androgenindependent prostate cancer, and that GSK3β is also involved in the regulation of the transactivation of the androgen receptor (AR) and growth of prostate cancer. Animal experiments have proved that some GSK3 inhibitors, such as lithium, can significantly suppress tumor growth in different animal models of prostate cancer. The GSK3 inhibitor is promising to be an important agent for the clinical management of prostate cancer.
Androgens ; Animals ; Cell Line, Tumor ; Glycogen Synthase Kinase 3 ; antagonists & inhibitors ; metabolism ; Glycogen Synthase Kinase 3 beta ; antagonists & inhibitors ; metabolism ; Humans ; Male ; Neoplasm Proteins ; metabolism ; Neoplasms, Hormone-Dependent ; enzymology ; metabolism ; Prostatic Neoplasms ; drug therapy ; enzymology ; pathology ; Receptors, Androgen ; metabolism

Prostaglandin synthase (PGS) can catalyze the production of various types of prostaglandins and regulate the expression levels of related substances. The regulation mechanisms of the PGS gene are closely related with the occurrence and development of prostate diseases. However, few studies are reported on the regulation mechanisms of PGS in prostatic diseases, such as benign prostatic hyperplasia (BPH) and prostate cancer (PCa), or on the relationship between PGS gene regulation and prostate diseases. This review aims to analyze their correlation and provide some ideas for the prevention and control of BPH and PCa by intervention of the prostaglandin synthase regulatory pathway.
Gene Expression Regulation ; Humans ; Male ; Prostaglandin-Endoperoxide Synthases ; genetics ; physiology ; Prostatic Hyperplasia ; enzymology ; genetics ; prevention & control ; Prostatic Neoplasms ; enzymology ; genetics ; prevention & control

ObjectiveTo explore the expression of I-5α-reductase (SRD5A1)and its prognostic role in prostate cancer .

METHODSData about SRD5A1 were retrieved from the ONCOMINE database and the role of SRD5A1 in prostate cancer was analyzed.

RESULTSTotally, 992 studies of different types relevant to the expression of SRD5A1 were identified in the ONCOMINE database. The SRD5A1 expression was statistically significant in 239 of the studies, overexpressed in 157 (11 in prostate cancer) and underexpressed in the other 82 (3 in prostate cancer). Eighteen of the studies, with 1 068 samples, addressed the expression of SRD5A1 in prostate cancer and normal tissues, which was significantly higher in the former than in the latter tissue (P<0.05). In 3 of the studies, the SRD5A1 expression was high in primary prostate cancer and increased with its metastasis (P<0.0 5). Two of the studies with prognostic data showed a higher rate of postoperative biochemical recurrence and a higher total mortality rate in the patients with a high than in those with a low expression of SRD5A1 (P<0.05).

CONCLUSIONSSRD5A1 is highly expressed in prostate cancer, especially in metastatic and castration-resistant prostate cancer and its expression is associated with the prognosis of prostate cancer, which may be an important target of medication for prostate cancer.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase ; metabolism ; Data Mining ; Humans ; Male ; Neoplasm Recurrence, Local ; Prognosis ; Prostatic Neoplasms ; enzymology ; mortality ; pathology ; surgery ; Prostatic Neoplasms, Castration-Resistant ; enzymology

ObjectiveTo explore the expression of pituitary tumor transforming gene 1 (PTTG1) during the transformation of prostate cancer from androgen-dependent (ADPC) to androgen-independent (AIPC).

METHODSWe established an AIPC cell model LNCaP-AI by culturing the androgen-dependent LNCaP cell line in the hormone-deprived medium for over 3 months. The cell model was verified and the PTTG1 expression in the LNCaP cells was detected by Western blot and RT-PCR during hormone deprivation.

RESULTSThe AIPC cell model LNCaP-AI was successfully established. The PTTG1 expression was gradually increased in the LNCaP cells with the prolonged time of hormone deprivation and the expressions of matrix metalloproteinases MMP-2 and -9 were elevated at the same time.

CONCLUSIONSThe expression of PTTG1 is increased gradually in AIPC, which may be a target of gene therapy for advanced prostate cancer.

Blotting, Western ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Matrix Metalloproteinase 2 ; metabolism ; Matrix Metalloproteinase 9 ; metabolism ; Neoplasms, Hormone-Dependent ; Prostatic Neoplasms ; enzymology ; genetics ; Securin ; genetics

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

OBJECTIVETo investigate the relationship between the polymorphisms of DNA methyltransferase (DNMT) and the risk and pathologic characteristics of prostate cancer (PCa) in Chinese men.

METHODSThis case-control study included 155 PCa patients and 155 healthy male controls. Using Sequenom MassARRAY, we detected the genotypes of the DNMT1 polymorphisms rs16999593 and rs2228611 and the DNMT3B polymorphism rs2424908, followed by analysis of their association with the risk and pathologic characteristics of prostate cancer by logistic regression.

RESULTSSignificant differences were found in the frequency of the rs16999593 genotypes (P = 0.041) and that of the rs2424908 genotypes (P = 0.025) between the case and control groups. The frequencies of the genotypes rs16999593CT (OR = 0.61, 95% CI 0.38-0.99, P = 0.043) and rs16999593CT/CC (OR = 0.59, 95% CI 0.39-0.92, P = 0.017) were obviously higher in the control than in the case group, and so were those of rs2424908CT (OR = 0.73, 95% CI 0.58-0.91, P = 0.007) and rs2424908CT/CC (OR = 0.57, 95% CI 0.36-0.94, P = 0.023). The frequencies of rs16999593CT/CC (OR = 0.47, 95% CI 0.28-0.85, P = 0.008) and rs2424908CT/CC (OR = 0.46, 95% CI 0.28-0.85, P = 0.009) were evidently lower in the cases with Gleason score < 7 than in the controls. However, none of the three polymorphisms ex hibited any significant differences in the frequencies of their genotypes between the patients with Gleason score > 7 and the healthy con trols (P > 0.05).

CONCLUSIONThe rs16999593CT/CC genotype of DNMT1 and the rs2424908CT/CC genotype of DNMT3B are as sociated with decreased risk of prostate cancer and lower Gleason score in C.

Aged ; Asian Continental Ancestry Group ; Case-Control Studies ; DNA (Cytosine-5-)-Methyltransferases ; genetics ; DNA Methylation ; Gene Frequency ; Genotype ; Humans ; Logistic Models ; Male ; Middle Aged ; Neoplasm Grading ; Polymorphism, Genetic ; Prostatic Neoplasms ; enzymology ; pathology ; Repressor Proteins ; genetics ; Risk