Mutational Analysis of Prostate-Specific Antigen Defines the Intrinsic Proteolytic Activity of the proPSA Zymogen.

Background: Prostate-specific antigen (PSA) is an important prostate cancer biomarker. It is also a protease expressed at high concentrations by the normal and malignant prostate. PSA is secreted as a zymogen (proPSA) with an inhibitory prodomain that must be removed for full activity.

Inhibitory control and the speech patterns of second language users.

Inhibitory control (IC), an ability to suppress irrelevant and/or conflicting information, has been found to underlie performance on a variety of cognitive tasks, including bilingual language processing. This study examines the relationship between IC and the speech patterns of second language (L2) users from the perspective of individual differences. While the majority of studies have supported the role of IC in bilingual language processing using single-word production paradigms, this work looks at inhibitory processes in the context of extended speech, with a particular emphasis on disfluencies.

Proteolysis of complement factors iC3b and C5 by the serine protease prostate-specific antigen in prostatic fluid and seminal plasma.

Prostate-specific Ag (PSA) is a serine protease that is expressed exclusively by normal and malignant prostate epithelial cells. The continued high-level expression of PSA by the majority of men with both high- and low-grade prostate cancer throughout the course of disease progression, even in the androgen-ablated state, suggests that PSA has a role in the pathogenesis of disease. Current experimental and clinical evidence suggests that chronic inflammation, regardless of the cause, may predispose men to prostate cancer.

Trypsin-like proteolytic contamination of commercially available psa purified from human seminal fluid.

Background: Prostate-Specific Antigen (PSA) is a serine protease whose expression is maintained in all stages of prostate cancer. A role for PSA in the pathobiology for prostate cancer has not been firmly established. Experimental studies to date support a role for PSA through mechanisms such as release or processing of growth factors and degradation of the extracellular matrix.

Progression of prostate carcinogenesis and dietary methyl donors: temporal dependence.

Insufficient dose of dietary methyl groups are associated with a host of conditions ranging from neural tube defects to cancer. On the other hand, it is not certain what effect excess dietary methyl groups could have on cancer. This is especially true for prostate cancer, a disease that is characterized by increasing DNA methylation changes with increasing grade of the cancer.

Enzymatically active prostate-specific antigen promotes growth of human prostate cancers.

Background: Prostate specific antigen (PSA) is the best-known member of the kallikrein-related peptidase family, with an established role as a prostatic disease biomarker. Although it is produced at high levels by all stages of prostate cancer, it is uncertain if PSA plays a role in prostate cancer initiation and progression. We decided to investigate the impact of PSA and its enzymatic activity on tumor cell growth rates.

Prostate-specific antigen (PSA) is activated by KLK2 in prostate cancer ex vivo models and in prostate-targeted PSA/KLK2 double transgenic mice.

Background: Prostate-specific antigen (PSA) is a serine protease secreted as a zymogen. Previously, cell-free biochemical studies have identified various kallikreins (KLK) as candidate activating proteases. In this study, KLK2-mediated activation of PSA in cell-based in vitro, xenograft, and transgenic models was evaluated.

Extended-release PEG-luciferin allows for long-term imaging of firefly luciferase activity in vivo.

Bioluminescence has gained favour in the last decade as an approach for observing tumours in vivo in a non-destructive manner. This very sensitive technique is based on light emission by the reaction of luciferin with the enzyme luciferase, as measured by a photodetector. Ever since the development of recombinant tumour cell lines that have been engineered to produce luciferase, a vast number of experiments have been carried out examining tumour growth, tumour metastasis and the effect of therapeutic regimens in such cases.

Mechanistic insights into the inhibition of prostate specific antigen by beta-lactam class compounds.

Prostate Specific Antigen (PSA) is a biomarker used in the diagnosis of prostate cancer and to monitor therapeutic response. However, its precise role in prostate carcinogenesis and metastasis remains largely unknown. A number of studies arguing in the favor of an active role of PSA in prostate cancer development and progression have implicated this serine protease in the release and activation of growth factors such as insulin-like growth factor 1 (IGF1) through cleavage of insulin like growth factor binding protein 3 and Transforming Growth Factor beta (TGF-beta) through cleavage of Latent TGF-beta.

Recombinant prostate-specific antigen proaerolysin shows selective protease sensitivity and cell cytotoxicity.

Native proaerolysin is a channel-forming bacterial protoxin that binds to cell-surface receptors and then is activated by furin or furin-like proteases. We genetically engineered proaerolysin by replacing the furin-cleavage sequence with a prostate-specific antigen-selective sequence. The recombinant modified proaerolysin was expressed and purified from Aeromonas salmonicida in good yields and purity.

Modulating paclitaxel bioavailability for targeting prostate cancer.

Four novel water-soluble peptide-paclitaxel conjugates were designed and synthesized as prostate-specific antigen (PSA)-activated prodrugs for prostate cancer therapy. These prodrugs were composed of a peptide, HSSKLQ or SSKYQ, each of which is selectively cleavable by PSA; a self-immolative linker, either para-aminobenzyl alcohol (PABS) or ethylene diamine (EDA); and the parent drug, paclitaxel. Introduction of a PABA or EDA linker between the peptide and paclitaxel in prodrugs 2-5 resulted in products with an increased rate of hydrolysis by PSA.

A prostate-specific antigen-activated channel-forming toxin as therapy for prostatic disease.

Background: Most men will develop prostatic abnormalities, such as benign prostatic hyperplasia (BPH) or prostate cancer, as they age. Prostate-specific antigen (PSA) is a serine protease that is secreted at high levels by the normal and diseased prostate. Therapies that are activated by PSA may prove effective in treating prostatic malignancies.

Does PSA play a role as a promoting agent during the initiation and/or progression of prostate cancer?

Prostate cancer cells, like normal prostate epithelial cells, produce high levels of the differentiation marker and serine protease prostate-specific antigen (PSA). PSA is used extensively as a biomarker to screen for prostate cancer, to detect recurrence following local therapies, and to follow response to systemic therapies for metastatic disease. While much is known about PSA's role as a biomarker, only a relatively few studies address the role played by PSA in the pathobiology of prostate cancer.

Bortezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells.

Bortezomib (PS-341, Velcade) is a peptide boronate inhibitor of the 20S proteasome that is currently being combined with taxanes in several clinical trials in patients with prostate cancer. Here, we report that bortezomib inhibited docetaxel-induced M-phase arrest and apoptosis in androgen-dependent LNCaP-Pro5 cells. Direct analysis of kinase activity in immune complex kinase assays revealed that docetaxel activated cyclin-dependent kinase (CDK) 1 (CDC2) and that bortezomib blocked this activation.

Comparative study of PSMA expression in the prostate of mouse, dog, monkey, and human.

Background: Intraprostatic PSMA targeted prodrugs/protoxins are under development in our laboratory. Future toxicologic studies of these therapies require identification of animal models that express PSMA within the prostate.

Method: PSMA enzymatic activity and protein expression was determined.

Bortezomib abolishes tumor necrosis factor-related apoptosis-inducing ligand resistance via a p21-dependent mechanism in human bladder and prostate cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines that induces apoptosis in some tumor cells but not in normal cells. Unfortunately, many human cancer cell lines are refractory to TRAIL-induced cell death, and the molecular mechanisms underlying resistance are unclear. Here we report that TRAIL resistance was reversed in human bladder and prostate cancer cell lines by the proteasome inhibitor bortezomib (PS-341, Velcade).

The proteasome inhibitor bortezomib stabilizes a novel active form of p53 in human LNCaP-Pro5 prostate cancer cells.

Advanced prostate cancer is resistant to current therapeutic strategies. Bortezomib (Velcade; previously called PS-341) is a potent and specific inhibitor of the 26S proteasome that is currently in clinical trials for treatment of various malignancies, including prostate cancer. We investigated the effects of bortezomib on p53 in the LNCaP-Pro5 prostate cancer cell line.