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)

An important factor implicated in tumor cell predisposition for invasion and metastasis is the malignancy-related upregulation of urokinase plasminogen activator receptor (uPAR). uPAR signals by activating different tyrosine kinases in different cells. We examined the effects of inhibiting uPAR signaling by inhibition of uPAR expression with antisense oligonucleotides (aODNs) in PC3 human prostate cancer cells and evaluated aODN effect in a mouse model of prostate cancer bone metastasis. Following uPAR aODN treatment, PC3 cells exhibited a strong decrease in uPAR expression, evaluated by flow cytometry and by polymerase chain reaction, and of FAK/JNK/Jun phosphorylation. The synthesis of cyclins A, B, D1 and D3 was inhibited, as shown by Western blotting, flow cytometry and polymerase chain reaction, and PC3 cells accumulated in the G2 phase of the cell cycle. PC3 cells' adhesion was unaffected, while proliferation and invasion of Matrigel were impaired. A total of 60 mice were subjected to intracardiac injection of PC3 cells and were randomly assigned to three groups: aODN (treated with 0.5 mg intraperitoneum/mouse/day), dODN (treated with the same amounts of a degenerated ODN) and control (injected with a saline solution). At 28 days after heart injection, mice were subjected to a digital scan of total body radiography, which revealed 80% reduction in mice affected by bone metastasis. The use of uPAR aODNs produced a substantial prophylactic effect against prostate cancer bone metastasis, which has to be ascribed to downregulation of uPAR expression.
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PMID:Effects of blocking urokinase receptor signaling by antisense oligonucleotides in a mouse model of experimental prostate cancer bone metastases. 1567 98

Prostate cancer is the second highest cause of cancer-related deaths of men in the US. Signal transducers and activators of transcription (STATs) proteins are a small family of latent cytoplasmic transcription factors that act downstream of Janus kinase (JAK) activation and mediate intracellular signaling from a wide variety of cytokines, growth factors, and hormones. Aberrant activation of STAT3 has been implicated in the progression of many human carcinomas, including prostate cancer. Previously, we have characterized a novel tyrosine kinase inhibitor peptide, Tkip, that is a mimetic of suppressor of cytokine signaling 1 (SOCS-1). Similar to SOCS-1, Tkip binds to the autophosphorylation site of JAK2 and inhibits phosphorylation of STAT1alpha. In this study, we determined the inhibitory effects of Tkip on the human prostate cancer cell lines DU145 and LNCaP. Tkip inhibited cellular proliferation of both DU145 and LNCaP cells, with a slightly greater antiproliferative effect on DU145 cells. Cell cycle analysis using flow cytometry showed Tkip blockage of progression into the S phase of the cell cycle. Tkip also inhibited constitutive (DU145) and IL-6-induced (LNCaP) activation of STAT3, consistent with the fact that STAT3 activation is mediated by JAK2. Tkip also slightly reduced the levels of cyclin D1, an important regulator of cell cycle progression into S phase, in DU145 and LNCaP cancer cell lines. These data describe a potentially important therapeutic that targets both constitutive and IL-6-induced STAT3 activation in human prostate cancer cell lines.
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PMID:A SOCS-1 peptide mimetic inhibits both constitutive and IL-6 induced activation of STAT3 in prostate cancer cells. 1568 10

Lipid rafts are cholesterol- and sphingolipid-enriched microdomains in cell membranes that regulate phosphorylation cascades originating from membrane-bound proteins. In this study, we tested whether alteration of the cholesterol content of lipid rafts in prostate cancer (PCa) cell membranes affects cell survival mechanisms in vitro and in vivo. Simvastatin, a cholesterol synthesis inhibitor, lowered raft cholesterol content, inhibited Akt1 serine-threonine kinase (protein kinase Balpha)/protein kinase B (Akt/PKB) pathway signaling, and induced apoptosis in caveolin- and PTEN-negative LNCaP PCa cells. Replenishing cell membranes with cholesterol reversed these inhibitory and apoptotic effects. Cholesterol also potentiated Akt activation in normal prostate epithelial cells, which were resistant to the apoptotic effects of simvastatin. Elevation of circulating cholesterol in SCID mice increased the cholesterol content and the extent of protein tyrosine phosphorylation in lipid rafts isolated from LNCaP/sHB xenograft tumors. Cholesterol elevation also promoted tumor growth, increased phosphorylation of Akt, and reduced apoptosis in the xenografts. Our results implicate membrane cholesterol in Akt signaling in both normal and malignant cells and provide evidence that PCa cells can become dependent on a cholesterol-regulated Akt pathway for cell survival.
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PMID:Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. 1577 12

Selective inhibition of repopulation of surviving tumor cells between courses of chemotherapy might improve the outcome of treatment. A potential target for inhibiting repopulation is the mammalian target of rapamycin pathway; PTEN-negative tumor cells are particularly sensitive to inhibition of this pathway. Here we study the rapamycin analogue CCI-779, alone or with chemotherapy, as an inhibitor of proliferation of the human prostate cancer cell lines PC-3 and DU145. The PTEN and phospho-Akt/PKB status and the effect of CCI-779 on phosphorylation of ribosomal protein S6 were evaluated by immunostaining and/or Western blotting. Expression of phospho-Akt/PKB in PTEN mutant PC-3 cells and xenografts was higher than in PTEN wild-type DU145 cells. Phosphorylation of S6 was inhibited by CCI-779 in both cell lines. Cultured cells were treated weekly with mitoxantrone or docetaxel for two cycles, and CCI-779 or vehicle was given between courses. Growth and clonogenic survival of both cell lines were inhibited in a dose-dependent manner by CCI-779, but there were minimal effects when CCI-779 was given between courses of chemotherapy. CCI-779 inhibited the growth of xenografts derived from both cell lines with greater effects against PC-3 than DU145 tumors. CCI-779 caused mild myelosuppression. The activity of mitoxantrone or docetaxel was limited, but CCI-779 given between courses of chemotherapy increased growth delay of PC-3 xenografts. Our results suggest that repopulation of PTEN-negative cancer cells between courses of chemotherapy might be inhibited by CCI-779.
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PMID:Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts. 1580 83

Clinical evidence links neuroendocrine differentiation (NED) to prostate cancer progression. In the prostate carcinoma PC-3 cell model, the action of the gastrin releasing peptide (GRP) analog, bombesin (BN), on the activation of focal adhesion kinase (FAK) and invasiveness suggests that this kinase might favor metastasis. Given that components of the FAK signalling pathway are also up regulated in prostate cancer, the aim of the present investigation was to test if FAK function is required for BN-induced motility in PC-3 cells. In wound assays designed to investigate the fate of FAK in cells undergoing BN-induced motility, it was observed that BN treatment resulted in relocalization of FAK in focal contacts concomitantly with its tyrosine phosphorylation on residue 397 (FAK [pY(397)]) and with the formation of actin lamellipodia. Moreover, BN-induced cell motility was significantly reduced in the presence of FAK inhibitors (either anti-FAK [pY(397)] antibody or FRNK, the FAK-related non-kinase). Altogether, these observations point towards a critical role for FAK in the action of BN on PC-3 cell motility.
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PMID:Focal adhesion kinase is required for bombesin-induced prostate cancer cell motility. 1586 27

Prostate adenocarcinoma metastasizes to the skeleton more frequently than any other organ. An underlying cause of this phenomenon may be the ability of bone-produced factors to specifically select disseminated prostate cancer cells that are susceptible to their trophic effects. Platelet-derived growth factor (PDGF), a potent mitogen for both normal and tumor cells, is produced in several tissues including bone, where it is synthesized by both osteoblasts and osteoclasts. Here, we show that PDGF causes a significantly stronger activation of the Akt/PKB survival pathway in bone-metastatic prostate cancer cells compared to nonmetastatic cells. Normal prostate epithelial cells and DU-145 prostate cells, originally derived from a brain metastasis, are not responsive to PDGF. In contrast, epidermal growth factor stimulates Akt to the same extent in all prostate cells tested. This difference in PDGF responsiveness depends on the higher expression of alpha-PDGFR in bone-metastatic compared to nonmetastatic prostate cells and the lack of alpha-PDGFR expression in normal and metastatic prostate cells derived from tissues other than bone. Thus, alpha-PDGFR expression might identify prostate cancer cells with the highest propensity to metastasize to the skeleton.
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PMID:Bone-metastatic potential of human prostate cancer cells correlates with Akt/PKB activation by alpha platelet-derived growth factor receptor. 1600 72

We have developed a simple analytical method that increases the efficiency of identifying mutant genes in cell lines after the inhibition of nonsense-mediated decay (NMD). The approach assumes that the spectra of mutant genes differ between cell lines of the same tumor origin. Thus, by analyzing more than one cell line in parallel and taking into account not only changes in mRNA levels after the inhibition of NMD, but also comparing mRNA levels between cell lines before the inhibition of NMD, the vast majority of false positives were eliminated from the analysis. In this study, we used Affymetrix oligonucleotide arrays to compare mRNA profiles of two prostate cancer cell lines, PC3 and LNCaP, before and after emetine treatment. As a result of our modified approach, from the 14,500 genes present on the array, 7 were identified as candidates from LNCaP cells and 1 was identified from PC3 cells. Sequence analysis of five of these candidate genes identified gene-inactivating mutations in four of them. Homozygous mutations were found in the synaptojanin 2 (SYNJ2) and the cleft lip and palate CLPTM1 genes. Two different heterozygous mutations in the Janus kinase 1 (JAK1) gene result in complete loss of the protein in several different prostate cancer cell lines.
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PMID:Identification of inactivating mutations in the JAK1, SYNJ2, and CLPTM1 genes in prostate cancer cells using inhibition of nonsense-mediated decay and microarray analysis. 1610 78

Metronomic chemotherapy refers to the close, regular administration of comparatively low doses of cytotoxic drugs, with minimal or no drug-free breaks, over prolonged periods. It is thought to have an antiangiogenic basis. However, whereas surprisingly durable and potent tumor responses have been observed in a number of preclinical tumor models, relapses usually eventually occur using this type of treatment strategy. We therefore decided to test modified metronomic chemotherapy regimens that might significantly delay such relapses, but still maintain modest and acceptable toxicity profiles. Here, we show that repeated administration of bolus doses (BDs) of cyclophosphamide every 3 or 6 weeks, combined with a daily oral low-dose metronomic (LDM) regimen (20 mg/kg/d cyclophosphamide), improves efficacy and significantly delays progression of transplanted PC-3 human prostate cancer xenografts, syngeneic transplanted EMT-6 breast tumors, and "spontaneous" murine erythroleukemia. Efficacy was superior whereas toxicity was mild and comparable to the LDM regimen, the latter assessed by body weight, neutrophil, lymphocyte, and total white blood counts. Antiangiogenic activity, measured by reduction in circulating endothelial precursor cells, revealed that the greatest degree of suppression occurred using the combination treatment. Overall, our results indicate that the administration of intermittent BD combined with chronic oral LDM cyclophosphamide is a potent treatment regimen for controlling tumor growth, which has a low toxicity profile, over prolonged periods of time.
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PMID:Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy. 1610 50

Androgen receptor plays a critical role in the development of primary as well as advanced hormone-refractory prostate cancer. Therefore, ablation of androgen receptor from prostate cancer cells is an interesting concept for developing a new therapy not only for androgen-dependent prostate cancer but also for metastatic hormone-refractory prostate cancer, for which there is no effective treatment available. We report here that LAQ824, a cinnamyl hydroxamatic acid histone deacetylase inhibitor currently in human clinical trials, effectively depleted androgen receptor in prostate cancer cells at nanomolar concentrations. LAQ824 seemed capable of depleting both the mutant and wild-type androgen receptors in either androgen-dependent and androgen-independent prostate cancer cells. Although LAQ824 may exert its effect through multiple mechanisms, several lines of evidence suggest that inactivation of the heat shock protein-90 (Hsp90) molecular chaperone is involved in LAQ824-induced androgen receptor depletion. Besides androgen receptor, LAQ824 reduced the level of Hsp90 client proteins HER-2 (ErbB2), Akt/PKB, and Raf-1 in LNCaP cells. Another Hsp90 inhibitor, 17-allyamino-17-demethoxygeldanamycin (17-AAG), also induced androgen receptor diminution. LAQ824 induced Hsp90 acetylation in LNCaP cells, which resulted in inhibition of its ATP-binding activity, dissociation of Hsp90-androgen receptor complex, and proteasome-mediated degradation of androgen receptor. Consequently, LAQ824 blocked androgen-induced prostate-specific antigen production in LNCaP cells. LAQ824 effectively inhibited cell proliferation and induced apoptosis of these prostate cancer cells. These results reveal that LAQ824 is a potent agent for depletion of androgen receptor and a potential new drug for prostate cancer.
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PMID:Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824. 1617 22

DNA methylation and copy number in the genomes of three immortalized prostate epithelial and five cancer cell lines (LNCaP, PC3, PC3M, PC3M-Pro4, and PC3M-LN4) were compared using a microarray-based technique. Genomic DNA is cut with a methylation-sensitive enzyme HpaII, followed by linker ligation, polymerase chain reaction (PCR) amplification, labeling, and hybridization to an array of promoter sequences. Only those parts of the genomic DNA that have unmethylated restriction sites within a few hundred base pairs generate PCR products detectable on an array. Of 2732 promoter sequences on a test array, 504 (18.5%) showed differential hybridization between immortalized prostate epithelial and cancer cell lines. Among candidate hypermethylated genes in cancer-derived lines, there were eight (CD44, CDKN1A, ESR1, PLAU, RARB, SFN, TNFRSF6, and TSPY) previously observed in prostate cancer and 13 previously known methylation targets in other cancers (ARHI, bcl-2, BRCA1, CDKN2C, GADD45A, MTAP, PGR, SLC26A4, SPARC, SYK, TJP2, UCHL1, and WIT-1). The majority of genes that appear to be both differentially methylated and differentially regulated between prostate epithelial and cancer cell lines are novel methylation targets, including PAK6, RAD50, TLX3, PIR51, MAP2K5, INSR, FBN1, and GG2-1, representing a rich new source of candidate genes used to study the role of DNA methylation in prostate tumors.
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PMID:Survey of differentially methylated promoters in prostate cancer cell lines. 1620 77


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