Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transcription factor signal transducer and activator of transcription (Stat)-3 is activated constitutively in prostate cancer (PCA) suggesting that its disruption could be an effective approach to control this malignancy. Here we assessed whether silibinin, a flavanone from Silybum marianum with proven anticancer efficacy in various cancer models, inhibits Stat3 activation in DU145 cells, and if it does, what is the biological fate of the cells? At 50 muM or higher concentrations for 24 or 48 h, silibinin concentration dependently reduced constitutive Stat3 phosphorylation at Tyr705 and Ser727 residues under both serum and serum-starved conditions. Constitutively active Stat3-DNA binding was also inhibited concentration dependently by silibinin; however, apoptotic death together with caspase and poly(ADP-ribose) polymerase (PARP) cleavage was observed by silibinin only under serum-starved conditions suggesting that additional survival pathways are active under serum conditions. In other studies, cells were treated with various specific pharmacological inhibitors where phosphorylation of Stat3 was not reduced by epidermal growth factor receptor and Mitogen activated protein/extracellular signal regulate kinase kinase (MEK1/2) inhibitors, suggesting lack of significant roles of these in Stat3 activation in DU145 cells. Janus kinase (JAK)-1 and JAK2 inhibitors strongly reduced Stat3 phosphorylation but did not result in apoptotic cell death. Interestingly, JAK1 inhibitor only in combination with silibinin resulted in a complete reduction in Stat3 phosphorylation at Tyr705, activated caspase-9 and caspase-3, and caused strong PARP cleavage and apoptotic death of DU145 cells. Given a critical role of Stat3 activation in PCA, our results showed that silibinin inhibits constitutively active Stat3 and induces apoptosis in DU145 cells, and thus might have potential significance in therapeutic intervention of this deadly malignancy.
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PMID:Silibinin inhibits constitutive activation of Stat3, and causes caspase activation and apoptotic death of human prostate carcinoma DU145 cells. 1734 59

Little is known about the role of the tumor suppressor gene phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in prostate cancer bone metastasis. To explore this, we used a pTetOn PTEN cell line in which PTEN expression was reconstituted in a PTEN-null bone metastatic human prostate cancer cell line, LnCaP-C4-2. We found that C4-2 cells selectively migrated toward conditioned medium from primary mouse calvaria cells compared with that derived from lung fibroblasts. Further evaluation with conditioned medium from an established mouse calvaria osteoblast cell line and control non-osteoblast cell line indicates that osteoblastic characteristics convey this specific migration to C4-2 cells. We evaluated promiscuously metastatic PC-3 prostate as well as T24T and UMUC-3 bladder cells and found they did not have a specific migratory response to calvaria-conditioned medium as did C4-2. Induction of PTEN expression inhibited the motility of C4-2 cells toward calvaria-conditioned medium but had no effect on migration toward lung-conditioned medium and this inhibitory effect was dependent on the PTEN lipid phosphatase activity. Calvaria- but not lung-conditioned medium induced activation of the small GTPase Rac1. Constitutively active Rac1 but not focal adhesion kinase or Cdc42 could rescue cells from the inhibitory effect of PTEN on cell migration and PTEN induction was observed to inhibit Rac1 activation in response to calvaria-conditioned medium. Our results support the notion that loss of PTEN function in human prostate cancer may specifically facilitate bone rather than other organ metastasis and suggest that Rac1, as a PTEN effector, may contribute to this metastatic tropism.
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PMID:The role of PTEN in prostate cancer cell tropism to the bone micro-environment. 1734 37

We describe a novel, potent peptide substrate mimetic inhibitor of protein kinase B (PKB/Akt). The compound selectively kills prostate cancer cells, in which PKB is highly activated, but not normal cells, or cancer cells in which PKB is not activated. The inhibitor induces apoptosis and inhibits the phosphorylation of PKB substrates in prostate cancer cell lines and significantly increases the efficacy of chemotherapy agents to induce prostate cancer cell death, when given in combination. In vivo, the inhibitor exhibits a strong antitumor effect in two prostate cancer mouse models. Moreover, treated animals develop significantly less lung metastases compared to untreated ones, and the effect is accompanied by a significant decrease in blood PSA [prostate-specific antigen] levels in treated animals. This compound and its potential analogues may be developed into novel, potent, and safe anticancer agents, both as stand-alone treatment and in combination with other chemotherapy agents.
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PMID:A novel substrate mimetic inhibitor of PKB/Akt inhibits prostate cancer tumor growth in mice by blocking the PKB pathway. 1739 40

Focal adhesions attach cultured cells to the extracellular matrix, and we found endogenous protein phosphatase-1alpha isoform (PP1alpha) localized in adhesions across the entire area of adherent fibroblasts. However, in fibroblasts migrating into a scrape wound or spreading after replating PP1alpha did not appear in adhesions near the leading edge but was recruited into other adhesions coincident in time and space with incorporation of tensin. Endogenous tensin and PP1alpha co-precipitated from cell lysates with isoform-specific PP1 antibodies. Chemical cross-linking of focal adhesion preparations with Lomant's reagent demonstrated molecular proximity of endogenous PP1alpha and tensin, whereas neither focal adhesion kinase nor vinculin was cross-linked and co-precipitated with PP1alpha, suggesting distinct spatial subdomains within adhesions. Transient expression of truncated tensin showed the N-terminal 360 residues, which comprise a protein-tyrosine phosphatase domain, alone were sufficient for isoform-selective co-precipitation of co-expressed PP1alpha. Human prostate cancer PC3 cells are deficient in tensin relative to fibroblasts and have fewer, mostly peripheral adhesions. Transient expression of green fluorescent protein tensin in these cancer cells induced formation of adhesions and recruited endogenous PP1alpha into those adhesions. Thus, the protein-tyrosine phosphatase domain of tensin exhibits isoform-specific association with PP1alpha in a restricted spatial region of adhesions that are formed during cell migration.
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PMID:Association of the tensin N-terminal protein-tyrosine phosphatase domain with the alpha isoform of protein phosphatase-1 in focal adhesions. 1743 17

Prostate cancer represents a major concern in human oncology and the phytoalexin resveratrol (RES) inhibits growth and proliferation of prostate cancer cells through the induction of apoptosis. In addition, previous data indicate that in oestrogen-responsive human breast cancer cells, RES induces apoptosis by inhibition of the phosphoinositide-3-kinase (PI3K) pathway. Here, using androgen receptor (AR)-positive LNCaP and oestrogen receptor alpha (ERalpha)-expressing PC-3 prostate tumour cells, we have analysed whether the antiproliferative activity of RES takes place by inhibition of the AR- or ERalpha-dependent PI3K pathway. Although RES treatment (up to 150 microM) decreased AR and ERalpha protein levels, it did not affect AR and ERalpha interaction with p85-PI3K. Immunoprecipitation and kinase assays showed that RES inhibited AR- and ERalpha-dependent PI3K activities in LNCaP and PC-3, respectively. Consistently, lower PI3K activities correlated with decreased phosphorylation of downstream targets protein kinase B/AKT (PKB/AKT) and glycogen synthase kinase-3 (GSK-3). GSK-3 dephosphorylation could be responsible for the decreased cyclin D1 levels observed in both cell lines. Importantly, RES markedly decreased PKB/AKT phosphorylation in primary cultures from human prostate tumours, suggesting that the mechanism proposed here could take place in vivo. Thus, RES could have antitumoral activity in androgen-sensitive and androgen-non-sensitive human prostate tumours by inhibiting survival pathways such as that mediated by PI3K.
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PMID:Non-genomic action of resveratrol on androgen and oestrogen receptors in prostate cancer: modulation of the phosphoinositide 3-kinase pathway. 1748 35

Today's treatment and diagnosis of prostate cancer still exhibit major limitations. The search for new and additional prognostic markers is therefore still an actual field of interest. Potential markers involved in numerous biological processes in the tumor cell have been investigated intensively. For therapeutic interventions it is important to distinguish between harmless and aggressive disease in an early stage. Therefore the subject of this review is limited to markers associated with those functional processes, which discriminate early stage aggressive, metastatic cancer from harmless disease. Important processes in this respect are: altered cell adhesion and cellular migration. E-cadherin, N-cadherin, beta-catenin, integrins, focal adhesion kinase, connexins and matrix metalloproteinases all appear promising biological markers associated with the early stage metastatic process in prostate cancer. Here we discuss their potential to become valid biological markers based on literature data. Thus far, none of these markers proved to be a valid individual marker by itself due to prostate cancer heterogeneity and transient expression. Analyzing a combination of the potential markers discussed in this review is expected to be a better approach toward discriminating high- from low-risk tumors in an early stage of prostate cancer.
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PMID:New experimental markers for early detection of high-risk prostate cancer: role of cell-cell adhesion and cell migration. 1752 Feb 86

We and other investigators have previously shown that membrane-type 1 matrix metalloproteinase (MT1-MMP) is overexpressed in invasive prostate cancer cells. However, the mechanism for this expression is not known. Here, we show that MT1-MMP is minimally expressed in nonmalignant primary prostate cells, moderately expressed in DU-145 cells, and highly expressed in invasive PC-3 and PC-3N cells. Using human MT1-MMP promoter reporter plasmids and mobility shift assays, we show that Sp1 regulates MT1-MMP expression in DU-145, PC-3, and PC-3N cells and in PC3-N cells using chromatin immunoprecipitation analysis and silencing RNA. Investigation of signaling pathway showed that DU-145 cells express constitutively phosphorylated extracellular stress-regulated kinase (ERK), whereas PC-3 and PC-3N cells express constitutively phosphorylated AKT/PKB and c-Jun NH2 terminal kinase (JNK). We show that MT1-MMP and Sp1 levels are decreased in PC-3 and PC-3N cells when phosphatidylinositol-3 kinase and JNK are inhibited, and that MT1-MMP levels are decreased in DU-145 cells when MEK is inhibited. Transient transfection of PC-3 and PC-3N cells with a dominant-negative JNK or p85, and of DU-145 cells with a dominant negative ERK, reduces MT1-MMP promoter activity. These results indicate differential signaling control of Sp1-mediated transcriptional regulation of MT1-MMP in prostate cancer cell lines.
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PMID:Membrane-type 1 matrix metalloproteinase is regulated by sp1 through the differential activation of AKT, JNK, and ERK pathways in human prostate tumor cells. 1753 46

Activated phosphoinositide 3-kinase (PI3K) and its downstream target Akt/PKB are important signaling molecules and key survival factors involved in the control of cell proliferation, apoptosis and oncogenesis. We investigated the role of the PI3K-Akt signaling pathway in the invasion of prostate cancer cell lines and activation of this pathway in primary human prostate tumors. Treatment of human prostate cancer cells viz. LNCaP, PC-3 and DU145 with PI3K pharmacological inhibitor, LY294002, potentially suppressed the invasive properties in each of these cell lines. Restoration of the PTEN gene to highly invasive prostate cancer PC-3 cells or expression of a dominant negative version of the PI3K target, Akt also significantly inhibited invasion and downregulated protein expression of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP)-9, markers for cell invasion, indicating a central role of the PI3K-Akt pathway in this process. Immunoblot analysis of PI3K and total/activated levels of Akt showed increased protein levels of catalytic (p110alpha/beta) and regulatory (p85) subunits of PI3K and constitutive Akt activation in high-grade tumors compared to low-grade tumor and benign tissue. Immunohistochemical analyses further confirmed a progressive increase in p-Akt (p-Ser473) levels but not of total-Akt (Akt1/2) in cancer tissues compared to benign specimens. A successive increase in p-Akt expression was further noted in specimens serially obtained from individuals with time-course disease progression. Taken together, these results suggest that aberrant activation of PI3K-Akt pathway may contribute to increased cell invasiveness and facilitate prostate cancer progression.
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PMID:Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. 1755 21

Aberrant regulation in the adhesive ability of cancer cells is closely associated with their metastatic activity. In this study, we examine the role of ErbB-2 in regulating the adhesive ability of androgen receptor (AR)-positive human prostate cancer (PCa) cells, the major cell population of PCa. Utilizing different LNCaP and MDA PCa2b cells as model systems, we found that ErbB-2 activity was correlated with PYK2 activity and adhesive ability in those cells. Increased ErbB-2 expression or activity in LNCaP C-33 cells enhanced PYK2 activation and cell adhesion, while the high PYK2 activity and the rapid adhesion of LNCaP C-81 cells were decreased by diminishing ErbB-2 expression or activity. Knockdown studies revealed the predominant role of ErbB-2 in regulating LNCaP C-81 cell adhesion. Coimmunoprecipitation showed that C-81 cells had increased interaction between ErbB-2 and PYK2. Elevated ErbB-2 activity in LNCaP cells correlated with increased ERK/MAPK activity and enhanced adhesive ability, which were abolished by the expression of K457A-PYK2 mutant or the treatment of PD98059, a MEK inhibitor. In summary, our data suggested that ErbB-2, via PYK2-ERK/MAPK, upregulates the adhesive ability of AR-positive human PCa cells.
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PMID:ErbB-2 via PYK2 upregulates the adhesive ability of androgen receptor-positive human prostate cancer cells. 1756 46

The main cause of prostate cancer-related mortality is the development of hormone-refractory disease. Circulating serum levels of IL-6 are raised in hormone-refractory prostate cancer patients and evidence from cell line studies suggests that the IL-6R/JAK/STAT3 pathway may be involved in development of this disease. In the current study we investigate if expression levels of these family members are implicated in the development of hormone-refractory prostate cancer. Immunohistochemistry using IL-6R, JAK1, STAT3, pSTAT3(Tyr705) and pSTAT3(Ser727) antibodies was performed on 50 matched hormone-sensitive and hormone-refractory tumours pairs. An increase in expression of cytoplasmic IL-6 receptor, with the development of hormone-refractory prostate cancer was associated with reduced time to relapse (P=0.0074) while an increase in expression of cytoplasmic pSTAT3(Tyr705) was associated with reduced patient survival (P=0.0003). In addition, those patients with high expression of cytoplasmic pSTAT3(Tyr705) in their hormone-refractory tumours had significantly shorter time to death from biochemical relapse and overall survival in comparison to those patients with low expression of cytoplasmic pSTAT3(Tyr705) (P=0.002 and P=0.0027, respectively). Activation of STAT3, via phosphorylation is associated with reduced patient survival, suggesting that activation of the IL-6R/JAK/STAT3 pathway is involved with development of hormone-refractory prostate cancer.
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PMID:Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer. 1759 57


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