Isolation and Structure Determination of an Imidazo-pyrimidine, 5-Chlorocavernicolin, Maleimide oximes and Nucleosides from a Marine Sponge Extract

In a continuation of our studies to discover bioactive secondary metabolites from marine sources, we further investigated samples from a tryptamine and phenyl-alkane producing sponge, which resulted in the isolation of four uncommon small molecules and five nucleosides. Their structures were determined to be 7,8-dihydroimidazo[1,5-c]pyrimidin-5(6H)-one (1), 5-chlorocavernicolin (2), maleimide-5-oxime (3), 3-methylmaleimide-5-oxime (4), uridine (5), 2'-deoxyuridine (6), thymidine (7), adenine (8), and adenosine (9) by spectroscopic analyses. The isolated compounds were evaluated for inhibitory activity against soluble epoxide hydrolase (sEH) as well as the Wnt/beta-catenine signaling pathway.

Clinical Significance of Wnt/beta-Catenin Signalling and Androgen Receptor Expression in Prostate Cancer

PURPOSE: To investigate the relationships among the Wnt/beta-catenin pathway, androgen receptor (AR), and clinicopathological factors in hormone-naive prostate cancer. MATERIALS AND METHODS: This study was conducted with132 cases of hormone-naive prostate cancer treated by prostatectomy and prostate needle biopsy. An immunohistochemical study using antibodies against beta-catenin, matrix metalloproteinase-7 (MMP-7), and the AR was performed. For the in vitro study, PC-3, LNCaP, 22Rv1, and DU145 cell lines were used. RESULTS: The clinical or pathological stage ware a localized cancer in 36 patients (27.3%), locally advanced cancer in 31 (23.5%), and metastatic cancer in 65 (49.2%). We detected increased beta-catenin, AR, and MMP-7 expression with a high Gleason grade, disease progression, and increasing serum prostate-specific antigen (PSA) levels (p<0.01). In Spearman's rank correlations, the expression of cytoplasmic beta-catenin, MMP-7, and the AR were found to be significantly positively correlated. In addition, the expression of beta-catenin, MMP-7, and the AR were significantly correlated with clinicopathological variables indicative of a poor prognosis. Forty-nine patients with primary androgen deprivation had short response durations from hormone therapy to PSA progression with elevated MMP-7 expression on the Kaplan-Meier curve (p=0.0036). CONCLUSIONS: These data show that an activated Wnt/beta-catenin pathway and AR expression in prostate cancer are correlated with metastasis and aggressiveness. In addition, the expression of MMP-7 protein, a target of the Wnt/beta-catenin pathway, is associated with PSA progression in prostate cancer patients undergoing primary hormone therapy.

Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the expression of beta-catenin, leading to a rapid proliferation of pancreatic cells

It is not yet understood how the enhanced expression of pancreatic adenocarcinoma up-regulated factor (PAUF; a novel oncogene identified in our recent studies), contributes to the oncogenesis of pancreatic cells. We herein report that PAUF up-regulates the expression and transcriptional activity of beta-catenin while the suppression of PAUF by shRNA down-regulates beta-catenin. The induction of beta-catenin by PAUF is mediated by the activities of Akt and GSK-3beta, but inhibition of downstream ERK does not reduce beta-catenin expression. To test whether PAUF emulates either the Wnt3a-mediated or the protein kinase A-mediated signaling pathway for the stabilization of beta-catenin, we examined the phosphorylation status of beta-catenin in the presence of PAUF compared with that of beta-catenin during treatment with Wnt3a or dibutyryl cAMP, a cell permeable cyclic AMP analogue. PAUF expression induces phosphorylation at Ser-33/37/Thr-41 and Ser-675 of beta-catenin but no phosphorylation at Ser-45, indicating that a unique phosphorylation pattern of beta-catenin is caused by PAUF. Finally, the expression of PAUF up-regulates both cyclin-D1 and c-Jun, target genes of beta-catenin, leading to a rapid proliferation of pancreatic cells; conversely decreased PAUF expression (by shRNA) results in the reduced proliferation of pancreatic cells. Treatment with hexachlorophene (an inhibitor of beta-catenin) reduces the proliferation of pancreatic cells despite the presence of PAUF. Taken together, we propose that PAUF can up-regulate and stabilize beta-catenin via a novel pattern of phosphorylation, thereby contributing to the rapid proliferation of pancreatic cancer cells.

Effect of Decursin on the Expression of beta-Catenin and Matrix Metalloproteinase-7 in Prostate Cancer Cell Lines / 대한비뇨기과학회지

PURPOSE: Alterations in the Wnt/beta-catenin pathway are associated with the development and progression of human prostate cancer. Decursin can attenuate the Wnt/beta-catenin pathway. We investigated the relationship between the Wnt/beta-catenin pathway and decursin in prostate cancer cells. MATERIALS AND METHODS: PC-3 and LNCaP cell lines were used. Cell viability was measured with methyl-thiazole tetrazolium bromide (MTT) assays, and cell apoptosis analysis was performed by FACScan. The amount of beta-catenin protein after treatment with decursin was measured by Western blot analysis. Expression of MMP-7 mRNA was detected by real-time polymerase chain reaction (RT-PCR). RESULTS: Death and apoptosis were increased after treatment with decursin 0.5-100 micrometer in PC-3 and LNCaP cells. This was revealed dose and time-dependent increase of cancer cell death on 24, 48 and 72 hours. FACScan showed an increment of apoptosis on 24, 48 hours. Expression of intracellular beta-catenin protein was decreased dose-dependently in both of prostate cancer cell lines. Decursin reduced MMP-7 mRNA expression on 6, 12, 24, 48 hours dose-dependently. CONCLUSIONS: Decursin affects the viability of prostate cancer cells. Increased cancer cell death was associated with increased apoptosis. This study suggests that decursin may play a role in the treatment of prostate cancer.

Expression of glucocorticoid receptor mRNAs in glucocorticoid-resistant nasal polyps

Glucocorticoids (GCs) are the most effective group of medications available to treat inflammation. Although most patients with inflammation respond to GC, a small group of patients exhibit persistent GC-resistance with prolonged inflammation. Previously, it was proposed that the GC-resistance is caused by low amount of human GC receptor (hGR alpha) and/or excessive presence of a GC receptor isoform, hGR beta that was generated from alternative splicing of the hGR message. We have tested this hypothesis by investigating correlation between the expression pattern of hGR mRNAs in patients with inflammatory nasal polyps and the effectiveness of GC treatment.? We have performed reverse transcription PCR analysis of mRNAs coding each hGR alpha and hGR beta in nasal tissues.? hGR alpha mRNA was more expressed in patients with nasal polyps than in normal subjects. However, the elevated hGR alpha mRNA expression was decreased after GC treatment. Compared with hGR alpha mRNA expression, level of hGR beta mRNA expression was very low in all groups. In patients, hGR beta mRNA was expressed at a similar level regardless of GC efficacy, indicating that there is no correlation between the GC sensitivity and the expression level of hGR beta mRNA. Thus, persistent GC-resistance is not associated with low expression of hGRa or over- expression of hGR beta.