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1.
Prostate ; 79(15): 1777-1788, 2019 11.
Article in English | MEDLINE | ID: mdl-31503357

ABSTRACT

BACKGROUND: Gleason grade is among the most powerful clinicopathological classification systems used to assess risk of lethal potential in prostate cancer, yet its biologic basis is poorly understood. Notably, pure low-grade cancers, comprised predominantly of Gleason pattern 3 (G3) are typically indolent, with lethal potential emerging with the progression of higher-grade Gleason patterns 4 (G4) or 5. One of the hallmarks of more aggressive cancer phenotypes is the stereotyped set of metabolic characteristics that transformed cells acquire to facilitate unregulated growth. In the present study, we profiled expression signatures of metabolic genes that are differentially expressed between G3 and G4 cancer foci and investigated the functional role of two of the profiled genes, PGRMC1 and HSD17B4, in prostate cancer cells. METHODS: Gene expression profiling was conducted using 32 G3 and 32 G4 cancer foci from patients with 3+3 and ≥4+3 tumors, respectively. A 95-gene Nanostring probe set was used to probe genes associated with energy metabolism. Two out of five genes (PGRMC1 and HSD17B4) that significantly distinguish between G3 and G4 were functionally validated in vitro using established prostate cancer cells (PC3, DU145). Expression of PGRMC1 and HSD17B4 was knocked down and subsequent studies were performed to analyze cell proliferation, migration, invasion, and apoptosis. Mechanistic studies that explored the epidermal growth factor receptor (EGFR) pathway were performed by Western blot. RESULTS: Multivariate analysis identified five metabolic genes that were differentially expressed between G3 and G4 stroma (P < .05). Functional validation studies revealed that knockdown of PGRMC1 and HSD17B4 significantly decreased cell proliferation, migration, and invasion, and increased apoptosis in PC3 and DU145 cells. Mechanistic studies showed that these effects, after PGRMC1 knockdown, were possibly mediated through alterations in downstream components of the EGFR, protein kinase B, and nuclear factor kappa-light-chain-enhancer of activated B cells pathways. CONCLUSION: The following study provides evidence supporting the use of metabolic genes PGRMC1 and HSD17B4 as a prognostic biomarker for the distinction between G3 and G4 prostate cancers.


Subject(s)
Gene Expression Regulation, Neoplastic , Prostate/pathology , Prostatic Neoplasms/genetics , Cell Line, Tumor , Disease Progression , Gene Expression Profiling , Humans , Male , Neoplasm Grading , Prostatic Neoplasms/pathology
2.
Prostate ; 79(2): 151-159, 2019 02.
Article in English | MEDLINE | ID: mdl-30242861

ABSTRACT

BACKGROUND: Cannabinoids have demonstrated anticarcinogenic properties in a variety of malignancies, including in prostate cancer. In the present study, we explored the anti-cancer effects of the synthetic cannabinoid WIN 55,212-2 (WIN) in prostate cancer. METHODS: Established prostate cancer cells (PC3, DU145, LNCaP) were treated with varying concentrations of WIN. Cell proliferation was determined by the MTS assay. The anti-migration and anti-invasive potential of WIN was examined by the wound healing assay and the matrigel invasion assay. Cell cycle analysis was performed by flow cytometry, and mechanistic studies were performed by Western blot. Athymic mice (n = 10) were inoculated with human PC3 cells. Once tumors reached 100 mm3 , animals were randomized into two groups: saline control and WIN (5 mg/kg), delivered by intraperitoneal injection three times per week for 3 weeks. RESULTS: WIN significantly reduced prostate cancer cell proliferation, migration, invasion, induced apoptosis, and arrested cells in Go/G1 phase in a dose-dependent manner. Mechanistic studies revealed these effects were mediated through a pathway involving cell cycle regulators p27, Cdk4, and pRb. Pre-treatment with a CB2 antagonist, AM630, followed by treatment with WIN resulted in a reversal of the anti-proliferation and cell cycle arrest previously seen with WIN alone. In vivo, administration of WIN resulted in a reduction in the tumor growth rate compared to control (P < 0.05). CONCLUSIONS: The following study provides evidence supporting the use of WIN as a novel therapeutic for prostate cancer.


Subject(s)
Benzoxazines/pharmacology , Morpholines/pharmacology , Naphthalenes/pharmacology , Prostatic Neoplasms/drug therapy , Receptor, Cannabinoid, CB2/metabolism , Animals , Apoptosis/drug effects , Cannabinoid Receptor Antagonists/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Interactions , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Indoles/pharmacology , Male , Mice , Mice, Nude , Neoplasm Invasiveness , PC-3 Cells , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Random Allocation , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Resting Phase, Cell Cycle/drug effects , Xenograft Model Antitumor Assays
3.
Anticancer Res ; 39(1): 113-118, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30591447

ABSTRACT

BACKGROUND/AIM: Desmopressin is a synthetic analogue of the antidiuretic hormone vasopressin. It has recently been demonstrated to inhibit tumor progression and metastasis in breast cancer models. Docetaxel is a chemotherapy agent for castrate-resistant prostate cancer (CRPC). In this study, the ability of CRPC cells to grow and develop in vivo tumors in an animal model was evaluated, in order to investigate the anti-tumor effect of desmopressin in combination with docetaxel. MATERIALS AND METHODS: The CRPC cell line PC3 was used for orthotopic inoculation in male athymic nude mice. The mice were randomly assigned to one of the four treatment groups: Control, docetaxel, desmopressin or combination therapy. Following the last treatment, tumors were excised and measured. Blood samples were processed for CTC analysis. RESULTS: Docetaxel treatment resulted in a significant reduction in tumor volume compared to control. The combination therapy resulted in even more significant reduction (31.2%) in tumor volume. There was a complete absence of CTCs in the combination group. CONCLUSION: Our pilot study demonstrated an enhanced efficacy of docetaxel-based therapy in combination with desmopressin.


Subject(s)
Deamino Arginine Vasopressin/administration & dosage , Docetaxel/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Male , Mice , Pilot Projects , Prostatic Neoplasms, Castration-Resistant/pathology , Tumor Burden , Xenograft Model Antitumor Assays
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