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

Aberrant activation of tyrosine kinases is linked causally to human cancers. Activated Cdc42-associated kinase (Ack1), an intracellular tyrosine kinase, has primarily been studied for its signaling properties but has not been linked to specific pathologic conditions. Herein, we report that expression of activated Ack1 in LNCaP cells, while minimally increasing growth in culture, enhanced anchorage-independent growth in vitro and dramatically accelerated tumorigenesis in nude mice. Molecular chaperone heat shock protein 90beta (Hsp90beta)-bound Ack1 and treatment of cells with geldanamycin, a Hsp90 inhibitor, inhibited Ack1 kinase activity and suppressed tumorigenesis. Further, we identify the tumor suppressor WW domain containing oxidoreductase (Wwox) as an Ack1-interacting protein. Activated Ack1 tyrosine phosphorylated Wwox, leading to rapid dissociation of the Ack1-Wwox complex and concomitant Wwox polyubiquitination followed by degradation. Tyrosine phosphorylation of Wwox was critical for its degradation, as splice variant WwoxDelta5-8 that was not phosphorylated by Ack1 failed to undergo polyubiquitination and degradation. It has been reported that phosphorylation of Wwox at Tyr33 stimulated its proapoptotic activity. We observed that Y33F Wwox mutant was still tyrosine phosphorylated and polyubiquitinated by Ack1 action. Site-directed mutagenesis revealed that activated Ack1 primarily phosphorylated Wwox at Tyr287, suggesting that phosphorylation of distinct tyrosine residues activate or degrade Wwox. Primary androgen-independent prostate tumors but not benign prostate showed increased tyrosine-phosphorylated Ack1 and decreased Wwox. Taken together, these data indicate that Ack1 stimulated prostate tumorigenesis in part by negatively regulating the proapoptotic tumor suppressor, Wwox. Further, these findings suggest that Ack1 could be a novel therapeutic target for prostate cancer.
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PMID:Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. 1628 44

Geldanamycin (GA), a benzoquinone ansamycin, is a naturally occurring inhibitor of heat shock protein (Hsp90), which regulates the transcription activity of hypoxia-inducible factor 1 (HIF-1alpha). Under hypoxia, HIF-1alpha is activated in tumor cells, and induces the transcription of vascular endothelial growth factor (VEGF), which is the prime regulator for angiogenesis. VEGF promotes the formation of new blood vessels by stimulating endothelial cell division and migration. This eventually forms a vascular network that allows for tumor growth and metastasis. In this study, we used GA to inhibit HIF-1alpha transcription function. Human prostate cancer DU-145 cells were incubated in a hypoxic chamber at 1% O(2) and 37 degrees C for different durations. Both mRNA and protein levels of HIF-1alpha and VEGF were upregulated under hypoxic conditions. We demonstrated that GA treatment of hypoxic DU-145 cells abolished the induction of HIF-1alpha protein in a time-dependent manner and decreased VEGF mRNA and its protein levels. The transient transfection of DU-145 cells with luciferase reporter gene construct (5HRE/hCMVmp-luc) showed that the transcriptional activity of HIF-1alpha was significantly induced in response to hypoxia, but inhibited by GA. In addition, using conditioned medium from GA-treated hypoxic cells led to a significant decrease in cell invasion in comparison with using conditioned medium from nontreated hypoxic cells. These data provide evidence for the important role of GA in inhibition of angiogenesis and also invasion mediated by HIF-1alpha in prostate cancer cells.
Prostate Cancer Prostatic Dis 2006
PMID:Effects of geldanamycin on HIF-1alpha mediated angiogenesis and invasion in prostate cancer cells. 1643 34

The immunological bases of current approaches to therapeutic cancer vaccination (or 'vacci-treatment') have been established for a decade or longer. The new developments lie mostly in the lessons learnt from clinical testing of these approaches. Three lessons are particularly worthy of note. First, recently completed randomized Phase 3 trials suggest that vacci-treatment with autologous dendritic cells expressing prostatic acid phosphatase (for prostate cancer) or with autologous tumor-derived heat shock protein (gp96)-peptide complexes show promise in enhancing survival of cancer patients. These two approaches are undergoing further randomized clinical testing. Second, immunological monitoring of many clinical trials has failed to identify a surrogate marker for clinical outcomes. Finally, an increasing volume of literature suggests that protective immunity to human cancers is elicited by the mutated antigenic repertoire unique to each cancer.
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PMID:Therapeutic cancer vaccines. 1646 65

Peptides spanning the range of human parathyroid hormone-related protein (PTHrP) have been shown to bind heat shock protein-70 expressed on the surface of cancer cells with cytoprotective consequences in vitro. The present study focused on identification of intracellular proteins that interact with the carboxy-terminal peptide of human PTHrP. Using affinity chromatography, we applied extracts of DU 145 prostate cancer cells over PTHrP (140-173)-Sepharose and eluted with 8 M urea. After concentration and electrophoresis, protein bands were excised and subjected to mass spectroscopy analyses. Proteins identified included those associated with protection from oxidative stress, DNA repair, protection from apoptosis, and proteins involved in membrane trafficking and cytoskeletal rearrangement. These novel protein-protein interactions further support the hypothesis that the carboxy-terminus of PTHrP plays a role in cell survival.
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PMID:Identification of DU 145 prostate cancer cell proteins that bind to the carboxy-terminal peptide of human PTHrP in vitro. 1651 10

Genistein is a candidate cancer chemopreventive drug being tested in clinical trials. We have shown that genistein blocks prostate cancer (PCa) cell invasion, that p38 mitogen-activated protein (MAP) kinase regulates activation of matrix metalloproteinase type 2 (MMP-2) and cell invasion, and that genistein prevents transforming growth factor beta (TGFbeta) from activating p38 MAP kinase. More recently, we identified MAP kinase-activated protein kinase 2 (MAPKAPK2) and the 27-kDa heat shock protein (HSP27) as downstream regulators of p38 MAP kinase. However, MAPKAPK2 and HSP27 can be regulated by factors other than p38 MAP kinase, and HSP27 is up-regulated during PCa progression. The current study was undertaken to examine the role of MAPKAPK2 and HSP27 in modulating genistein-mediated regulation of PCa cell invasion. Genistein inhibited TGFbeta-mediated phosphorylation of MAPKAPK2 and HSP27. Inhibitory effects by genistein upon cell signaling, inhibition of MMP-2, and inhibition of invasion were retained when both PC3 and PC3-M cells were transfected with either wild-type MAPKAPK2 or HSP27. However, transfection with dominant-negative MAPKAPK2 or nonphosphorylatable mutant HSP27 led to decreases in cell invasion and to abrogation of responsiveness to either TGFbeta-mediated increases or genistein-mediated decreases in MMP-2 and cell invasion. It is noteworthy that, after transfection with constitutive active MAPKAPK2 or with pseudophosphorylated HSP27, levels of MMP-2 activation and cell invasion were high and overcame any inhibitory effect of genistein. These findings demonstrate that genistein-mediated inhibition of cell invasion rests upon blocking activation of the MAPKAPK2-HSP27 pathway, and that its activation during cancer progression has the potential to mitigate therapeutic efficacy.
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PMID:Genistein inhibits matrix metalloproteinase type 2 activation and prostate cancer cell invasion by blocking the transforming growth factor beta-mediated activation of mitogen-activated protein kinase-activated protein kinase 2-27-kDa heat shock protein pathway. 1677 19

Thermal therapy efficacy can be diminished due to heat shock protein (HSP) induction in regions of a tumor where temperatures are insufficient to coagulate proteins. HSP expression enhances tumor cell viability and imparts resistance to chemotherapy and radiation treatments, which are generally employed in conjunction with hyperthermia. Therefore, an understanding of the thermally induced HSP expression within the targeted tumor must be incorporated into the treatment plan to optimize the thermal dose delivery and permit prediction of the overall tissue response. A treatment planning computational model capable of predicting the temperature, HSP27 and HSP70 expression, and damage fraction distributions associated with laser heating in healthy prostate tissue and tumors is presented. Measured thermally induced HSP27 and HSP70 expression kinetics and injury data for normal and cancerous prostate cells and prostate tumors are employed to create the first HSP expression predictive model and formulate an Arrhenius damage model. The correlation coefficients between measured and model predicted temperature, HSP27, and HSP70 were 0.98, 0.99, and 0.99, respectively, confirming the accuracy of the model. Utilization of the treatment planning model in the design of prostate cancer thermal therapies can enable optimization of the treatment outcome by controlling HSP expression and injury.
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PMID:Optimizing heat shock protein expression induced by prostate cancer laser therapy through predictive computational models. 1696 41

Environmental xenobiotics have been shown to act as endocrine disruptors and to be implicated in increased cancer susceptibility. In particular, there is a significant concern regarding the impact of these contaminants on prostate cancer development and progression. However, the mechanisms with which these contaminants exert their detrimental effects are yet unclear and need to be further elucidated. In the present study, we investigated the effects of Aroclor-1254, a mixture of more than 60 environmental pollutants belonging to the polychlorinated biphenyl family, on rat prostate primary cultures. The results obtained after 24-h exposure indicated the ability of this contaminant mixture to influence mRNA stability and length of the 3'-end poly(A)tail of Connexin-32, Connexin-43, and heat shock protein-70. Consistent with this observation, immunostaining experiments demonstrated the altered availability of the encoded proteins. We also focused our attention on possible effects of Aroclor-1254 on cell morphology and could detect ultrastructural changes with gap junction disruption, fusion of single cells into clusters, and different aspects of apoptosis that became evident when exposure to Aroclor-1254 was extended to 72 h. The effects on the nuclear compartment were confirmed by the results obtained with Comet assay that showed DNA decompression and double-strand breaks already after 24-h exposure. Taken together, these findings show a detrimental effect of Aroclor 1254 on rat prostate cells and indicate a possible association between exposure to polychlorinated biphenyl mixture and induction of transformation process in prostate cells.
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PMID:Aroclor-1254 affects mRNA polyadenylation, translational activation, cell morphology, and DNA integrity of rat primary prostate cells. 1763 42

Androgen receptor (AR) is a ligand-activated transcription factor belonging to the steroid hormone receptor family and is very important for the development and progression of prostate cancer. The soy isoflavone genistein has been shown previously to down-regulate AR in androgen-dependent prostate cancer cell lines such as LNCaP. However, the mechanism(s) by which AR is down-regulated by genistein is still not known fully. We show a new mechanism by which genistein inhibits AR protein levels. We show that genistein-treated LNCaP cells exhibit increased ubiquitination of AR, suggesting that AR protein is down-regulated via a proteasome-mediated pathway. AR is normally stabilized by the chaperone activity of the heat shock protein Hsp90. The increased ubiquitination of AR after genistein treatment is attributed to decreased Hsp90 chaperone activity as assessed by its increased functionally inactive acetylated form. Consistent with this result, we find that HDAC6, which is a Hsp90 deacetylase, is inhibited by the antiestrogenic activity of genistein. Hence, in this study, we elucidate a novel mechanism of AR down-regulation by genistein through inhibition of HDAC6-Hsp90 cochaperone function required to stabilize AR protein. Our results suggest that genistein could be used as a potential chemopreventive agent for prostate cancers along with known inhibitors of HDAC6 and Hsp90.
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PMID:Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function. 1885 23

The vast majority of breast and prostate cancers express specific receptors for steroid hormones, which play a pivotal role in tumor progression. Because of the efficacy of endocrine therapy combined with its relatively mild side-effects, this intervention has nowadays become the treatment of choice for patients with advanced breast and prostate cancer, provided that their tumors express hormone receptors. However, in case of breast cancer it is well known that part of the patients have hormone receptor-negative tumors at diagnosis, whereas other patients have discordant receptor expression across lesions. In addition, receptor expression can change during therapy and result in resistance to this therapy. Besides several lines of hormonal treatments, also other strategies to affect the hormone receptors are currently under investigation, namely histone deacetylases (HDAC) and heat shock protein (HSP) inhibitors. Knowledge of the actual receptor status can support optimal treatment decision-making and the evaluation of new drugs. Positron emission tomography (PET) is a non-invasive nuclear imaging technique that allows monitoring and quantification of hormone receptor expression across lesions throughout the body. Several PET tracers have been developed for imaging of the most relevant hormone receptors in breast and prostate cancer: i.e. the estrogen, progesterone and androgen receptors. Some of these PET tracers have been successfully applied in early clinical studies. This review will give an overview of the current status of PET imaging of hormone receptors in breast and prostate cancer.
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PMID:PET imaging of steroid receptor expression in breast and prostate cancer. 1899 16

Cancer-derived heat shock protein gp96 induces a tumor-specific protective immune response primarily mediated by cytotoxic T lymphocytes (CTL) directed toward cancer-associated peptides associated with gp96. Both innate and adaptive immune responses have been demonstrated using a cell culture-based signaling mechanism. When used as an extraneous vaccine, one critical interaction which must occur for an immune response to be generated is the interaction between gp96 and the antigen presenting cell (APC) surface receptors (CD91, SR-A, TLR-2, and TLR-4). Our previous study concluded that gp96 purified from various rat and human prostate cancers is differentially glycosylated based on the amino and neutral monosaccharide content, and it was postulated that the monosaccharides may play a role in its biological activity. In this report, we report differences in the cancer-specific sialic acid content of gp96 purified from normal rat prostate compared to two rat prostate cancers, MAT-LyLu and Dunning G, as well as between two human prostate cancer cells, LnCaP and DU145. We also examined the modulatory effect of sialic acid residues on the binding of gp96 to APCs and its subsequent activation. Our results supported the contention that significant differences in the sialic acid content exist between Dunning G, MAT-LyLu, and normal rat prostate gp96, which affected its binding and biochemical activity to APCs. We therefore postulate that varied glycans of HPS96, a hitherto neglected structural component, may play a pivotal role in its anticancer activity. We suggest that construction of the glycan tree is a key to identification of the necessary and sufficient elements in the structure-function activity of HSP96.
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PMID:Sialic acid content of tissue-specific gp96 and its potential role in modulating gp96-macrophage interactions. 1957 60


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