UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously found that selective restriction of amino acids inhibits invasion of two androgen-independent human prostate cancer cell lines, DU145 and PC3. Here we show that the restriction of tyrosine (Tyr) and phenylalanine (Phe), methionine (Met) or glutamine (Gln) modulates the activity of G proteins and affects the balance between two actin-binding proteins, cofilin and profilin, in these two cell lines. Selective amino acid restriction differentially reduces G protein binding to GTP in DU145 cells. Tyr/Phe deprivation reduces the amount of Rho-GTP and Rac1-GTP. Met deprivation reduces the amount of Ras-GTP and Rho-GTP, and Gln deprivation decreases Ras-GTP, Rac-GTP, and Cdc42-GTP. Restriction of these amino acids increases the amount of profilin, cofilin and phosphorylation of cofilin-Ser(3). Increased PAK1 expression and phosphorylation of PAK1-Thr(423), and Ser(199/204) are consistent with the increased phosphorylation of LIMK1-Thr(508). In PC3 cells, Tyr/Phe or Gln deprivation reduces the amount of Ras-GTP, and all of the examined amino acid restrictions reduce the amount of profilin. PAK1, LIMK1 and cofilin are not significantly altered. These data reveal that specific amino acid deprivation differentially affects actin dynamics in DU145 and PC3. Modulation on Rho, Rac, PAK1, and LIMK1 likely alter the balance between cofilin and profilin in DU145 cells. In contrast, profilin is inhibited in PC3 cells. These effects modulate directionality and motility to inhibit invasion.
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PMID:Selective amino acid restriction differentially affects the motility and directionality of DU145 and PC3 prostate cancer cells. 1845 46

This study identifies a novel mechanism by which thiazolidinediones mediate cyclin D1 repression in prostate cancer cells. Based on the finding that the thiazolidinedione family of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists mediated PPARgamma-independent cyclin D1 degradation, we developed a novel PPARgamma-inactive troglitazone derivative, STG28, with high potency in cyclin D1 ablation. STG28-mediated cyclin D1 degradation was preceded by Thr-286 phosphorylation and nuclear export, which however, were independent of glycogen synthase kinase 3beta. Mutational analysis further confirmed the pivotal role of Thr-286 phosphorylation in STG28-induced nuclear export and proteolysis. Of several kinases examined, inhibition of IkappaB kinase alpha blocked STG28-mediated cytoplasmic sequestration and degradation of cyclin D1. Pulldown of ectopically expressed Cul1, the scaffold protein of the Skp-Cullin-F-box E3 ligase, in STG28-treated cells revealed an increased association of cyclin D1 with beta-TrCP, whereas no specific binding was noted with other F-box proteins examined, including Skp2, Fbw7, Fbx4, and Fbxw8. This finding represents the first evidence that cyclin D1 is targeted by beta-TrCP. Moreover, beta-TrCP expression was up-regulated in response to STG28, and ectopic expression and small interfering RNA-mediated knock-down of beta-TrCP enhanced and protected against STG28-facilitated cyclin D1 degradation, respectively. Because cyclin D1 lacks the DSG destruction motif, mutational and modeling analyses indicate that cyclin D1 was targeted by beta-TrCP through an unconventional recognition site, (279)EEVDLACpT(286), reminiscent to that of Wee1. Moreover, we obtained evidence that this beta-TrCP-dependent degradation takes part in controlling cyclin D1 turnover when cancer cells undergo glucose starvation, which endows physiological relevance to this novel mechanism.
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PMID:A novel mechanism by which thiazolidinediones facilitate the proteasomal degradation of cyclin D1 in cancer cells. 1865 Apr 23

In recent years, the use of natural products for cancer prevention and treatment has received considerable attention. Bryostatin 1 is a natural macrocyclic lactone and a protein kinase D (PKD) modulator with potent antineoplastic properties that has been used to treat human cancers in clinical trials with limited success. Further understanding the mechanistic basis of Bryostatin 1 action may provide opportunities to improve clinical results of treatment with Bryostatin 1. We identified that PKD1, founding member of PKD family of serine/threonine kinases, modulates E-cadherin/beta-catenin activity, which plays an important role in cell integrity, polarity, growth, and morphogenesis. An aberrant expression and localization of E-cadherin/beta-catenin has been strongly associated with cancer progression and metastasis. In this study, we examined the effect of Bryostatin 1 treatment on PKD1 activation, beta-catenin translocation and transcription activity, and malignant phenotype of prostate cancer cells. Initial activation of PKD1 with Bryostatin 1 leads to colocalization of the cytoplasmic pool of beta-catenin with PKD1, trans-Golgi network markers, and proteins involved in vesicular trafficking. Activation of PKD1 by Bryostatin 1 decreases nuclear beta-catenin expression and beta-catenin/TCF transcription activity. Activation of PKD1 alters cellular aggregation and proliferation in prostate cancer cells associated with subcellular redistribution of E-cadherin and beta-catenin. For the first time, we have identified that Bryostatin 1 modulates beta-catenin signaling through PKD1, which identifies a novel mechanism to improve efficacy of Bryostatin 1 in clinical settings.
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PMID:Bryostatin 1 modulates beta-catenin subcellular localization and transcription activity through protein kinase D1 activation. 1876 27

Preclinical studies have implicated the mammalian target of rapamycin (mTOR) pathway in the cell cycle progression and growth of prostate cancer cells. Downstream signaling from PI3'-K/Akt leads to phosphorylation (p) of mTOR at serine 2448 and to activation of its substrate, p70S6Kinase (p70S6K), phosphorylated on threonine 389. This promotes translation and cell cycle progression. Morphoproteomic analysis, that combines both the application of phosphospecific probes directed against putative sites of activation on protein analytes and cellular compartmentalization [1] was carried out on tissue microarray (TMA) slides from 64 cases of primary, previously untreated adenocarcinomas of the prostate. Gleason scores ranged from 6 to 10. High grade prostatic intraepithelial neoplasia (HGPIN), which accompanied the invasive cancer in 20 cases, and 15 non-neoplastic controls from benign prostatic hypertrophy specimens in a separate TMA were also included. Ninety-three percent (93%) of tumors exhibited moderate to strong cytoplasmic/plasmalemmal expression of p-mTOR and eighty-five percent (85%) showed similar staining intensity for p-p70S6K. HGPIN demonstrated comparable and occasionally, stronger expression levels for these protein analytes. Quantitative digital imaging revealed an overall increase in the mean expression levels in HGPIN, reaching statistical significance for p-mTOR (Ser 2448) at p<0.05. Morphoproteomic analysis confirms the constitutive activation of the mTOR pathway in prostate cancer and HGPIN, with relative overexpression of p-mTOR in HGPIN. These findings coincide with preclinical studies in supporting a role for the mTOR pathway in the biology and development of prostate cancer through its putative precursor lesion, HGPIN and in suggesting a potential therapeutic target.
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PMID:Morphoproteomic confirmation of a constitutively activated mTOR pathway in high grade prostatic intraepithelial neoplasia and prostate cancer. 1878 12

Protein kinase D (PKD) is a novel family of serine/threonine kinases targeted by the second messenger diacylglycerol. It has been implicated in many important cellular processes and pathological conditions. However, further analysis of PKD in these processes is severely hampered by the lack of a PKD-specific inhibitor that can be readily applied to cells and in animal models. We now report the discovery of the first potent and selective cell-active small molecule inhibitor for PKD, benzoxoloazepinolone (CID755673). This inhibitor was identified from the National Institutes of Health small molecule repository library of 196,173 compounds using a human PKD1 (PKCmu)-based fluorescence polarization high throughput screening assay. CID755673 suppressed half of the PKD1 enzyme activity at 182 nm and exhibited selective PKD1 inhibition when compared with AKT, polo-like kinase 1 (PLK1), CDK activating kinase (CAK), CAMKIIalpha, and three different PKC isoforms. Moreover, it was not competitive with ATP for enzyme inhibition. In cell-based assays, CID755673 blocked phorbol ester-induced endogenous PKD1 activation in LNCaP cells in a concentration-dependent manner. Functionally, CID755673 inhibited the known biological actions of PKD1 including phorbol ester-induced class IIa histone deacetylase 5 nuclear exclusion, vesicular stomatitis virus glycoprotein transport from the Golgi to the plasma membrane, and the ilimaquinone-induced Golgi fragmentation. Moreover, CID755673 inhibited prostate cancer cell proliferation, cell migration, and invasion. In summary, our findings indicate that CID755673 is a potent and selective PKD1 inhibitor with valuable pharmacological and cell biological potential.
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PMID:Potent and selective disruption of protein kinase D functionality by a benzoxoloazepinolone. 1882 54

beta-Catenin is essential for E-cadherin-mediated cell adhesion in epithelial cells and also acts as a key cofactor for transcription activity. We previously showed that protein kinase D1 (PKD1), founding member of the PKD family of signal transduction proteins, is down-regulated in advanced prostate cancer and interacts with E-cadherin. This study provides evidence that PKD1 interacts with and phosphorylates beta-catenin at Thr(112) and Thr(120) residues in vitro and in vivo; mutation of Thr(112) and Thr(120) results in increased nuclear localization of beta-catenin and is associated with altered beta-catenin-mediated transcription activity. It is known that mutation of Thr(120) residue abolishes binding of beta-catenin to alpha-catenin, which links to cytoskeleton, suggesting that PKD1 phosphorylation of Thr(120) could be critical for cell-cell adhesion. Overexpression of PKD1 represses beta-catenin-mediated transcriptional activity and cell proliferation. Epistatic studies suggest that PKD1 and E-cadherin are within the same signaling pathway. Understanding the molecular basis of PKD1-beta-catenin interaction provides a novel strategy to target beta-catenin function in cells including prostate cancer.
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PMID:Protein kinase D1-mediated phosphorylation and subcellular localization of beta-catenin. 1914 52

Phosphorylation on certain Ser/Thr-Pro motifs is a major oncogenic mechanism. The conformation and function of phosphorylated Ser/Thr-Pro motifs are further regulated by the prolyl isomerase Pin1. Pin1 has been shown to be prevalently overexpressed in human breast cancer cell lines and cancer tissues and to play a critical role in the transformation of mammary epithelial cells by activating multiple oncogenic pathways. Pin1 expression was found to be an excellent independent prognostic marker in prostate cancer. However, little is known about Pin1 and its downstream targets beta-catenin and cyclin D1 expressions in human oral cancers. In the present study, we quantified Pin1 expression in 74 paired normal/tumor human oral cancer samples as well as oral cancer cell lines. Pin1 was overexpressed in oral squamous cell carcinoma (OSCC) and its level correlated with beta-catenin accumulation and cyclin D1 expression. Moreover, we examined Pin1 mRNA expression in OSCC and cancer cell lines by RT-PCR analysis. The results showed that there is concordance in the relationship between the Pin1 mRNA level and Pin1 protein expression. The up-regulation of Pin1 mRNA expression in tumor part when comparing with that in non-tumor part was in agreement with that of the Pin1 protein overexpressed in OSCC. In addition, we showed that the molecular and immunohistochemical profiles of Pin1 overexpression were associated with progression of OSCC. Taken together, these results indicate that Pin1 is a regulator of cyclin D1 expression in OSCC and might play a role in oral oncogenesis. The overexpression of Pin1 can be used as an indicator for pathological diagnosis of OSCC.
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PMID:Pin1 overexpression is associated with poor differentiation and survival in oral squamous cell carcinoma. 1928 14

Taxol has been widely used as an anticancer drug for ovarian, breast, lung and prostate cancer. Some kinds of Taxus plants are widely distributed in the Northeast Asia region. We have isolated seven tricyclic diterpenoids, taxinine, taxagifine, 5-O-cinnamoyltaxacin I triacetate, 5-decinnamoyltaxinine J, 5-cinnamoyl-9-acetyltaxicin I, taxacin and taxol from the needles of Taxus media var. Hicksii, and investigated their effects on stimulus-induced superoxide generation and translocation of cytosolic compounds to the cell membrane in human neutrophils. Six tricyclic diterpenoids used in this experiment suppressed the superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) and arachidonic acid (AA) in a concentration-dependent manner. Taxinine significantly suppressed the superoxide generation induced by phorbol 12-myristate 13-acetate (PMA). The compounds also suppressed fMLP- and AA-induced tyrosyl or PMA-induced serine/threonine phosphorylation, and translocation of cytosolic compounds, p47 (phox), p67 (phox) and Rac to the cell membrane in parallel with the suppression of the stimulus-induced superoxide generation.
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PMID:Effect of seven tricyclic diterpenoids from needles of Taxus media var. Hicksii on stimulus-induced superoxide generation, tyrosyl or serine/threonine phosphorylation and translocation of cytosolic compounds to the cell membrane in human neutrophils. 1928 1

In this study, we compare the proteasome inhibition capabilities of two anticancer candidates, [Ni(L(IA))(2)] (1) and [Zn(L(IA))(2)] (2), where L(IA-) is the deprotonated form of the ligand 2,4-diiodo-6-(((2-pyridinylmethyl)amino)methyl)phenol. Species 1 contains nickel(II), a considerably inert ion that favors covalency, whereas 2 contains zinc(II), a labile transition metal ion that favors predominantly ionic bonds. We report on the synthesis and characterization of 1 and 2 using various spectroscopic, spectrometric, and structural methods. Furthermore, the pharmacological effects of 1 and 2, along with those of the salts NiCl(2) and ZnCl(2), were evaluated in vitro and in cultured human cancer cells in terms of their proteasome-inhibitory and apoptotic cell-death-inducing capabilities. It is shown that neither NiCl(2) nor 1 have the ability to inhibit the proteasome activity at any sustained levels. However, ZnCl(2) and 2 showed superior inhibitory activity versus the chymotrypsin-like activity of both the 26S proteasome (IC(50) = 5.7 and 4.4 micromol/L, respectively) and the purified 20S proteasome (IC(50) = 16.6 and 11.7 micromol/L, respectively) under cell-free conditions. Additionally, inhibition of proteasomal activity in cultured prostate cancer cells by 2 was associated with higher levels of ubiquitinated proteins and apoptosis. Treatment with either the metal complex or the salt was relatively nontoxic toward human normal cells. These results strengthen the current working hypothesis that fast ligand dissociation is required to generate an [ML(IA)](+) pharmacophore, capable of interaction with the proteasome. This interaction, possibly via N-terminal threonine amino acids present in the active sites, renders the proteasome inactive. Our results present a compelling rationale for 2 along with its gallium(III) and copper(II) congeners to be further investigated as potential anticancer drugs that act as proteasome inhibitiors.
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PMID:Comparative activities of nickel(II) and zinc(II) complexes of asymmetric [NN'O] ligands as 26S proteasome inhibitors. 1949 41

Androgen receptor (AR) is phosphorylated at multiple sites in response to ligand binding, but the functional consequences and mechanisms regulating AR phosphorylation remain to be established. We observed initially that okadaic acid, an inhibitor of the major PPP family serine/threonine phosphatases PP2A and protein phosphatase 1 (PP1), had cell type-dependent effects on AR expression. More specific inhibitors of PP2A (fostriecin) and PP1 (tautomycin and siRNA against the PP1alpha catalytic subunit) demonstrated that PP1 and protein phosphatase 2A had opposite effects on AR protein and transcriptional activity. PP1 inhibition enhanced proteasome-mediated AR degradation, while PP1alpha overexpression increased AR expression and markedly enhanced AR transcriptional activity. Coprecipitation experiments demonstrated an AR-PP1 interaction, while immunofluorescence and nuclear-cytoplasmic fractionation showed androgen-stimulated nuclear translocation of both AR and PP1 in prostate cancer cells. Studies with phosphospecific AR antibodies showed that PP1 inhibition dramatically increased phosphorylation of Ser-650, a site in the AR hinge region shown to mediate nuclear export. Significantly, PP1 inhibition caused a marked decrease in nuclear localization of the wild-type AR, but did not alter total or nuclear levels of a S650A mutant AR. These findings reveal a critical role of PP1 in regulating AR protein stability and nuclear localization through dephosphorylation of Ser-650. Moreover, AR may function as a PP1 regulatory subunit and mediate PP1 recruitment to chromatin, where it can modulate transcription and splicing.
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PMID:Androgen receptor phosphorylation and activity are regulated by an association with protein phosphatase 1. 1962 40

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