BackgroundINPP4B and PTEN dual specificity phosphatases are frequently lost during progression of prostate cancer to metastatic disease. We and others have previously shown that loss of INPP4B expression correlates with poor prognosis in multiple malignancies and with metastatic spread in prostate cancer.ResultsWe demonstrate that de novo expression of INPP4B in highly invasive human prostate carcinoma PC-3 cells suppresses their invasion both in vitro and in vivo. Using global gene expression analysis, we found that INPP4B regulates a number of genes associated with cell adhesion, the extracellular matrix, and the cytoskeleton. Importantly, de novo expressed INPP4B suppressed the proinflammatory chemokine IL-8 and induced PAK6. These genes were regulated in a reciprocal manner following downregulation of INPP4B in the independently derived INPP4B-positive LNCaP prostate cancer cell line. Inhibition of PI3K/Akt pathway, which is highly active in both PC-3 and LNCaP cells, did not reproduce INPP4B mediated suppression of IL-8 mRNA expression in either cell type. In contrast, inhibition of PKC signaling phenocopied INPP4B-mediated inhibitory effect on IL-8 in either prostate cancer cell line. In PC-3 cells, INPP4B overexpression caused a decline in the level of metastases associated BIRC5 protein, phosphorylation of PKC, and expression of the common PKC and IL-8 downstream target, COX-2. Reciprocally, COX-2 expression was increased in LNCaP cells following depletion of endogenous INPP4B.ConclusionTaken together, we discovered that INPP4B is a novel suppressor of oncogenic PKC signaling, further emphasizing the role of INPP4B in maintaining normal physiology of the prostate epithelium and suppressing metastatic potential of prostate tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-014-0061-y) contains supplementary material, which is available to authorized users.
The tumor suppressor INPP4B is an important regulator of phosphatidyl-inositol signaling in the cell. Reduced INPP4B expression is associated with poor outcomes for breast, prostate, and ovarian cancer patients. INPP4B contains a CX5R catalytic motif characteristic of dual-specificity phosphatases, such as PTEN. Lipid phosphatase activity of INPP4B has previously been described. In this report we show that INPP4B can dephosphorylate para-nitrophenyl phosphate (pNPP) and 6,8-difluoro-4-methylumbelliferyl (DiFMUP), synthetic phosphotyrosine analogs, suggesting that INPP4B has protein tyrosine phosphatase (PTP) activity. Using mutagenesis, we examined the functional role of specific amino acids within the INPP4B C842KSAKDR catalytic site. The K843M mutant displayed increased pNPP hydrolysis, the K846M mutant lost lipid phosphatase activity with no effect on PTP activity, and the D847E substitution ablated PTP activity and significantly reduced lipid phosphatase activity. Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and PTP activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation. Taken together our data identified key residues in the INPP4B catalytic domain associated with lipid and protein phosphatase activities and found a robust downstream target regulated by INPP4B but not PTEN.
Abstract• As the French national forest inventory does not currently monitor the lying compartment of the forest deadwood, the figures obtained on this topic are therefore partial. This study provides cost estimates and guidelines for assessing stumps, and standing and lying deadwood.• Comparisons were made between a fixed-area sampling method and a line-intersect one. LIS was judged more time-efficient, especially in dense understorey. Computer simulations were performed in order to estimate the gain in precision with increasing transect lengths. The results showed a continuous improvement in precision associated with increases in transect length. The longest transect tested (50 m) still had a large coefficient of variation, suggesting that improvement in precision at the plot level could still be gained with longer transects.• Therefore, from a practical standpoint in terms of fieldwork, we suggest that on a national scale lying deadwood should be measured by line-intersect sampling, whereas stumps, standing dead trees and snags can be monitored using standard fixed-area plots. To meet needs at the national level, we consider that local imprecision could be compensated for by the large number of plots measured each year. Mots-clés :bois mort / échantillonnage linéaire / échantillonnage par placette à surface fixe / inventaire forestier national Résumé -Étude préliminaire de l'évaluation du volume de bois mort à l'Inventaire forestier national français.• L'inventaire forestier national français ne réalise pas l'inventaire du bois mort au sol, les résultats à ce sujet sont donc partiels. Cette étude donne des orientations en termes de coûts et de méthode pour l'échantillonnage des souches, arbres morts debout et le bois mort au sol.• Les méthodes d'inventaire par placette à surface fixe et échantillonnage linéaire ont été comparées. L'échantillonnage linéaire a été jugé plus rapide surtout lorsque le sous-bois est dense. Des simulations ont été réalisées pour estimer le gain de précision avec l'augmentation de la longueur de transect. Les résultats ont montré une amélioration continue de la précision associée à l'augmentation de la longueur de transect. Le transect le plus long testé (50 m) a toujours un coefficient de variation élevé ; ce qui suggère que l'amélioration de la précision à l'échelle du point peu être obtenue avec un transect plus long.• Du point de vue pratique au niveau du travail de terrain, nous suggérons qu'à l'échelle nationale le bois mort au sol soit mesuré par transect alors que les souches, arbres morts debout et chandelles soit mesurées avec la méthode standard des placettes fixes. Afin de satisfaire aux besoins de l'échelle nationale, nous avons considéré que l'imprécision locale peut être compensée par le nombre important de points mesurés chaque année.
Purpose Castration therapy in advanced prostate cancer eventually fails and leads to development of castration resistant prostate cancer (CRPC) which has no cure. Characteristic features of CRPC can be increased androgen receptor (AR) expression and altered transcriptional output. We investigated expression of Nuclear Receptor Corepressor 1 (NCOR1) in human prostate and prostate cancer and the role of NCOR1 in response to antiandrogens. Experimental Design NCOR1 protein levels were compared between matched normal prostate and prostate cancer in 409 patient samples. NCOR1 knockdown was used to investigate its effect on bicalutamide response in androgen-dependent prostate cancer cell lines and transcriptional changes associated with loss of NCOR1. NCOR1 transcriptional signature was also examined in prostate cancer gene expression datasets. Results NCOR1 protein was detected in cytoplasm and nuclei of secretory epithelial cells in normal prostate. Both cytoplasmic and nuclear NCOR1 protein levels were lower in prostate cancer than in normal prostate. Prostate cancer metastases show significant decrease in NCOR1 transcriptional output. Inhibition of LNCaP cellular proliferation by bicalutamide requires NCOR1. NCOR1 regulated genes suppress cellular proliferation and mediate bicalutamide resistance. In mouse, NCOR1 is required for bicalutamide dependent regulation of a subset of the AR target genes. Conclusions In summary, we demonstrated that NCOR1 function declines with prostate cancer progression. Reduction in NCOR1 levels causes bicalutamide resistance in LNCaP cells and compromises response to bicalutamide in mouse prostate in vivo.
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