Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human glandular kallikrein (KLK2) is a highly prostate-specific serine protease, which is mainly excreted into the seminal fluid, but part of which is also secreted into circulation from prostatic tumors. Since the expression level of KLK2 is elevated in aggressive tumors and it has been suggested to mediate the metastasis of prostate cancer, inhibition of the proteolytic activity of KLK2 is of potential therapeutic value. We have previously identified several KLK2-specific linear peptides by phage display technology. Two of its synthetic analogs, A R R P A P A P G (KLK2a) and G A A R F K V W W A A G (KLK2b), show specific inhibition of KLK2 but their sensitivity to proteolysis in vivo may restrict their potential use as therapeutic agents. In order to improve the stability of the linear peptides for in vivo use, we have prepared cyclic analogs and compared their biological activity and their structural stability. A series of cyclic variants with cysteine bridges were synthesized. Cyclization inactivated one peptide (KLK2a) and its derivatives, while the other peptide (KLK2b) and its derivatives remained active. Furthermore, backbone cyclization of KLK2b improved significantly the resistance against proteolysis by trypsin and human plasma. Nuclear magnetic resonance studies showed that cyclization of the KLK2b peptides does not make the structures more rigid. In conclusion, we have shown that backbone cyclization of KLK2 inhibitory peptides can be used to increase stability without losing biological activity. This should render the peptides more useful for in vivo applications, such as tumor imaging and prostate cancer targeting.
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PMID:Activity and stability of human kallikrein-2-specific linear and cyclic peptide inhibitors. 1743 44

Human prostate-specific antigen (PSA), a 33 kDa serine protease with comprehensive homology to glandular kallikrein, is secreted from prostatic tissue into the seminal fluid and enters into the circulation. The level of PSA increases in the serum of patients with prostatic cancer and hence is widely employed as a marker of the disease status. In particular, an enzymatically active PSA that is a form cleaved at the N-terminal seven-amino-acids prosequence, APLILSR, of proPSA may play an important roll in the progression of prostate cancer. Thus, the presence of the active form would selectively discriminate the cancer from benign prostatic hyperplasia. In this study, we developed a convenient purification method for the acquisition of active PSA and proPSA. Recombinant proPSA and active PSA were expressed directly in Escherichia coli, easily and efficiently isolated from inclusion bodies, refolded, and purified. Moreover, the enzymatic activity of the recombinant active PSA was confirmed as serine protease using chromogenic chymotrypsin substrate. This purified active PSA could be further applied to scrutinize the biological or conformational characteristics of the protein and to develop specific diagnostic and/or therapeutic agents against prostate cancer.
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PMID:Expression and purification of recombinant active prostate-specific antigen from Escherichia coli. 1805 7

Research into actions of resveratrol, abundantly present in red grape skin, has been greatly stimulated by its reported beneficial health influence. Since it was recently proposed as a potential prostate cancer chemopreventive agent, we here performed an in vivo experiment to explore its effect in the Transgenic Rat for Adenocarcinoma of Prostate (TRAP) model, featuring the rat probasin promoter/SV 40 T antigen. Resveratrol suppressed prostate cancer growth and induction of apoptosis through androgen receptor (AR) down-regulation, without any sign of toxicity. Resveratrol not only downregulated androgen receptor (AR) expression but also suppressed the androgen responsive glandular kallikrein 11 (Gk11), known to be an ortholog of the human prostate specific antigen (PSA), at the mRNA level. The data provide a mechanistic basis for resveratrol chemopreventive efficacy against prostate cancer.
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PMID:Suppression of prostate cancer growth by resveratrol in the transgenic rat for adenocarcinoma of prostate (TRAP) model. 1843 64

A major characteristic of prostate cancer is the elevation of serum levels of prostate-specific antigen (hK3) and hK2, which are tumor markers that correlate with advancing stages of disease. Including hK4, these three kallikrein serine proteases are almost exclusively produced by the prostate. Prostate cancer cells have been recently shown to overexpress protease-activated receptors (PAR), which can be potentially activated by kallikreins and can regulate tumor growth. Here, we show that recombinant hK2 and hK4 activate ERK1/2 signaling of DU-145, PC-3, and LNCaP prostate cancer cells, which express both PAR1 and PAR2. These kallikreins also stimulate the proliferation of DU-145 cells. Pretreatment of hK2 and hK4 with the serine protease inhibitor, aprotinin, blocks the responses in DU-145 cells, and small interfering RNA against PAR1 and PAR2 also inhibits ERK1/2 signaling. To determine which PAR is activated by hK2 and hK4, a cell line that expresses a single PAR, a PAR1 knockout mouse lung fibroblast cell line transfected with PAR1 (KOLF-PAR1) or PAR2 (KOLF-PAR2) was used. hK4 activates both PAR1 and PAR2, whereas hK2 activates PAR2. hK4 generates more phosphorylated ERK1/2 than hK2. These data indicate that prostatic kallikreins (hK2 and hK4) directly stimulate prostate cancer cell proliferation through PAR1 and/or PAR2 and may be potentially important targets for future drug therapy for prostate cancer.
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PMID:Prostate-specific kallikreins-2 and -4 enhance the proliferation of DU-145 prostate cancer cells through protease-activated receptors-1 and -2. 1856 7

The prostate produces several proteases, the most abundant ones being kallikrein-related peptidase 3 (KLK3, PSA) and KLK2 (hK2), which are potential targets for tumor imaging and treatment. KLK3 expression is lower in malignant than in normal prostatic epithelium and it is further reduced in poorly differentiated tumors, in which the expression of KLK2 is increased. KLK3 has been shown to inhibit angiogenesis, whereas KLK2 may mediate tumor growth and invasion by participating in proteolytic cascades. Thus, it may be possible to control prostate cancer growth by modulating the proteolytic activity of KLK3 and KLK2. We have developed peptides that very specifically stimulate the activity of KLK3 or inhibit that of KLK2. Using these peptides we have established peptide-based methods for the determination of enzymatically active KLK3. The first-generation peptides are unstable in vivo and are rapidly cleared from the circulation. Currently we are modifying the peptides to make them suitable for in vivo applications. We have been able to considerably improve the stability of KLK2-binding peptides by cyclization. In this review we summarize the possible roles of KLK3 and KLK2 in prostate cancer and then concentrate on the development of peptides that modulate the activity of these proteases.
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PMID:Development of peptides specifically modulating the activity of KLK2 and KLK3. 1862 44

To investigate the expressions of PIM-1 and hK2 mRNA in normal prostate, benign prostatic glandular hyperplasia (BPH), and prostate cancer (PCa), and to explore the association of PIM-1 and hK2 expressions with PCa progression. The samples were harvested from 37 patients with BPH, 23 patients with PCa, and three with normal prostate tissues. Total RNA was extracted from their prostate tissues and analyzed for PIM-1 and hK2 mRNA levels using SYBR green I-based quantitative real-time RT-PCR (QRT-PCR) assays and Southern blot analysis. The differences of gene expressions were calculated based on standard curve. Quantitative expressions of PIM-1 and hK2 mRNA in normal prostate, BPH, and PCa were 1.05 +/- 0.04, 2.57 +/- 0.74, 4.45 +/- 0.63, and 1.02 +/- 0.03, 2.264 +/- 0.46, 5.905 +/- 0.78, respectively. PIM-1 and hK2 were expressed higher in PCa than those in BPH and normal prostate tissues, the differences among which had statistic significance (P < 0.05). Our results support the hypothesis that PIM-1 and hK2 play a significant role in the growth of PCa and the detection of PIM-1 and hK2 mRNA expressions by QRT-PCR provided more reliable and helpful information on diagnosis, treatment, and prognosis of PCa.
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PMID:Real-time quantitative RT-PCR assessment of PIM-1 and hK2 mRNA expression in benign prostate hyperplasia and prostate cancer. 1900 46

The introduction of total prostate-specific antigen (tPSA) testing in serum has revolutionized the detection and management of men with prostate cancer. This review will highlight some of the exciting new developments in the field of prostate cancer screening in general and from our SPORE research program at Memorial-Sloan Kettering Cancer Center. First, it is important to understand that the inherent variability of tPSA levels affects the interpretation of any single results. Total variation in tPSA includes both analytical (i.e., pre-analytical sample handling, laboratory processing, assay performance, and standardization) and biological variation (i.e., metabolism, renal elimination, medication, physical and sexual activity, size and integrity of the prostate). Second, recent evidence demonstrates that no single tPSA cut-off separates men at high risk for prostate cancer from men at low risk or men with "significant" (high grade, high volume) cancer from those with low grade, indolent cancer. Taken together with a man's age, family history, ethnicity, and digital rectal exam results, tPSA levels add to the overall estimate of the risk of cancer, allowing men to share in the decision about a biopsy. Third, men who will eventually develop prostate cancer have increased tPSA levels years or decades before the cancer is diagnosed. These tPSA levels may reflect the long duration of prostate carcinogenesis and raise the question about a causal role for tPSA in prostate cancer development and progression. Total prostate-specific antigen measurements before age 50 could help risk stratify men for intensity of prostate cancer screening. Fourth, enhancing the diagnostic accuracy of tPSA, especially its specificity, is of particular importance, since higher specificity translates into fewer biopsies in men not affected by prostate cancer. While tPSA velocity has been shown to improve the specificity of tPSA, its sensitivity is too low to avoid prostate biopsy in a patient with an elevated tPSA level. Moreover, prospective screening studies have reported that tPSA velocity does not add diagnostic value beyond tPSA level. At this time, tPSA velocity appears most useful after diagnosis and after treatment, but its value in screening and prognostication remains to be shown. Finally, while free PSA molecular isoforms and human kallikrein-related peptidase 2 (hK2) hold the promise for detection, staging, prognosis, and monitoring of prostate cancer, evidence from large prospective clinical trials remain to be reported.
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PMID:Screening for prostate cancer: an update. 1904 89

Available chemotherapeutics take advantage of the fast proliferation of cancer cells. Consequently slow growth makes androgen refractory prostate cancer resistant towards available drugs. No treatment is available at the present, when the cancer has developed metastases outside the prostate (T4 stage). Cytotoxins killing cells irrespective of the phase of the cell cycle will be able to kill slowly proliferating prostate cancer cells. Lack of selectivity, however, prevents their use as systemic drugs. Prostate cancer cells secrete characteristic proteolytic enzymes, e.g. PSA and hK2, with unusual substrate specificity. Conjugation of cytotoxins with peptides, which are selective substrates for PSA or hK2, will afford prodrugs, from which the active drug only will be released in close vicinity of the cancer cells. Based on this strategy prodrugs targeted at prostate cancer cells have been constructed and evaluated as potential drugs for prostate cancer. The potency of the thapsigargins as apoptotic agents make these naturally occurring sesquiterpene lactones attractive lead compounds. Intensive studies on structure-activity relationships and chemistry of the thapsigargins have enabled construction of potent derivatives enabling conjugation with peptides. Studies on the mechanism of action of the thapsigargins have revealed that the cytoxicity is based on their ability to inhibit the intracellular sarco-/endoplasmtic calcium pump.
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PMID:A Trojan horse in drug development: targeting of thapsigargins towards prostate cancer cells. 1927 21

The kallikrein, prostate-specific antigen (PSA), is one of the world's most frequently used disease biomarkers. After almost two decades of research and clinical experience, the diagnostic and monitoring limitations of PSA are beginning to be understood. Most physicians are aware of PSA's low specificity for cancer among older men with benign prostatic conditions; fewer are aware of recent data, which show that a prior negative biopsy or a prior PSA value below the threshold for biopsy might compromise the predictive accuracy of PSA even further. Furthermore, a subtle increase in serum PSA level during early middle age is strongly correlated with clinically important prostate cancer. We review current and past reports on the prostate kallikreins PSA and hK2 in relation to pathology and epidemiology.
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PMID:Prostate kallikrein markers in diagnosis, risk stratification and prognosis. 1957 55

We have previously reported that the increase in c-Jun expression induced by quercetin inhibited androgen receptor (AR) transactivation, and Sp1 was involved in quercetin-mediated downregulation of AR activity. Transient transfection assays in this work revealed that co-expression of c-Jun quenched Sp1-induced production of luciferase activity driven by AR promoter or three copies of Sp1 binding elements in the AR promoter. Moreover, c-Jun repressed AR-mediated luciferase activity via androgen-response elements (AREs) of the hK2 gene, while this suppression could be restored partially by cotransfection of Sp1 expression plasmid. The physical associations of c-Jun, Sp1, and AR induced by quercetin were further demonstrated by co-immunoprecipitation experiments. In addition, quercetin-mediated repression of AR expression and activity was partially reversed by blocking of JNK signaling pathway. These results suggested that c-Jun might play an important role in the suppression of AR expression and activity in the presence of quercetin, and association of a c-Jun/Sp1/AR protein complex induced by quercetin represented a novel mechanism that was involved in down-regulation of the AR function in prostate cancer cells.
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PMID:Suppression of the androgen receptor function by quercetin through protein-protein interactions of Sp1, c-Jun, and the androgen receptor in human prostate cancer cells. 2014 54


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