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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The most frequent site of metastasis in human prostate cancer (PCa) is the bone. Preferential adhesion of PCa cells to bone-specific factors may facilitate the selective metastasis of the skeleton. The most abundant protein within the skeleton is type I collagen. We previously demonstrated that PCa cells selected in vitro for collagen I binding (LNCaP(col)) are highly motile and acquired the capacity to grow within the bone compared to nontumorigenic LNCaP parental cells. Treatment with alpha(2)beta(1)-neutralizing antibodies selectively blocked collagen-stimulated migration, suggesting that integrin signaling mediates PCa migration. To elucidate the mechanism of collagen-stimulated migration, we evaluated integrin-associated signaling pathways in non-collagen-binding LNCaP parental cells and in collagen-binding isogenic C4-2B and LNCaP(col) PCa cells. The expression and activity of RhoC guanosine triphosphatase was increased five- to eightfold in collagen-binding LNCaP(col) and C4-2B cells, respectively, compared to parental LNCaP cells. RhoC activation was selectively blocked with antibodies to alpha(2)beta(1) where treatment with a small hairpin RNA specific for RhoC suppressed collagen-mediated invasion without altering the PCa cells' affinity for collagen I. We conclude that the ligation of alpha(2)beta(1) by collagen I activates RhoC guanosine triphosphatase, which mediates PCa invasion, and suggests a mechanism for the preferential metastasis of PCa cells within the bone.
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PMID:Type I collagen receptor (alpha2beta1) signaling promotes prostate cancer invasion through RhoC GTPase. 1867 Jun 40

TMSG-1 was a tumor metastasis-related gene identified using mRNA differential display, whose expression level was lower in cancer cell lines with higher metastatic potential and in tumor tissue with metastasis. TMSG-1 was transfected to prostate cancer cell line (PC-3M-1E8) with high metastatic potential to observe the effects of increased expression of TMSG-1 on V-ATPase activity, intracellular pH and cell apoptosis. Subcellular localization of the encoded protein of TMSG-1 was determined by using GFP. Results showed that there were no differences of V-ATPase activity among parental PC-3M-1E8 cell line, pcDNA3 transfectant and anti-TMSG-1 transfectant, whereas the V-ATPase activity was significantly higher in TMSG-1 transfectant than that in parental PC-3M-1E8 cell line, pcDNA3 transfectant and Anti-TMSG-1 transfectant (p<0.001). Intracellular pH (pHi) was detected by using the pH-dependent fluorescence probe BECEF. Results showed the pHi was significantly increased in TMSG-1 transfectant. Cell apoptosis assay demonstrated cell apoptosis was significantly higher in -1 transfectant (p<0.01) and BCL2 expression was down regulated. Subcellular localization of TMSG-1 protein showed TMSG-1 was a transmembrane protein, which predicted TMSG-1 protein was located in cytoplasm system, such as endoplasmic reticulum and mitochondrial. These results indicated TMSG-1 up regulation in prostate cancer cell line could promote V-ATPase activity, increase pHi and cell apoptosis, and inhibit the expression of BCL2.
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PMID:Primary functional identification of gene TMSG-1. 1875 21

Dynamic modulation of cell adhesion is integral to a wide range of biological processes. The small guanosine triphosphatase (GTPase) Rap1 is an important regulator of cell-cell and cell-matrix adhesions. We show here that induced expression of activated Abl tyrosine kinase reduces Rap1-GTP levels through phosphorylation of Tyr221 of CrkII, which disrupts interaction of CrkII with C3G, a guanine nucleotide exchange factor for Rap1. Abl-dependent down-regulation of Rap1-GTP causes cell rounding and detachment only when the Rho-ROCK1 pathway is also activated, for example, by lysophosphatidic acid (LPA). During ephrin-A1-induced retraction of PC3 prostate cancer cells, we show that endogenous Abl is activated and disrupts the CrkII-C3G complex to reduce Rap1-GTP. Interestingly, ephrin-A1-induced PC3 cell retraction also requires LPA, which stimulates Rho to a much higher level than that is activated by ephrin-A1. Our results establish Rap1 as another downstream target of the Abl-CrkII signaling module and show that Abl-CrkII collaborates with Rho-ROCK1 to stimulate cell retraction.
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PMID:Induction of cell retraction by the combined actions of Abl-CrkII and Rho-ROCK1 signaling. 1900 Nov 22

Factors that drive prostate cancer progression remain poorly defined, thus hindering the development of new therapeutic strategies. Disseminated tumors are treated through regimens that ablate androgen signaling, as prostate cancer cells require androgen for growth and survival. However, recurrent, incurable tumors that have bypassed the androgen requirement ultimately arise. This study reveals that the Brm ATPase, a component of selected SWI/SNF complexes, has significant antiproliferative functions in the prostate that protect against these transitions. First, we show that targeted ablation of Brm is causative for the development of prostatic hyperplasia in mice. Second, in vivo challenge revealed that Brm-/- epithelia acquire the capacity for lobe-specific, castration-resistant cellular proliferation. Third, investigation of human specimens revealed that Brm mRNA and protein levels are attenuated in prostate cancer. Fourth, Brm down-regulation was associated with an increased proliferative index, consistent with the mouse model. Lastly, gene expression profiling showed that Brm loss alters factors upstream of E2F1; this was confirmed in murine models, wherein Brm loss induced E2F1 deregulation in a tissue-specific manner. Combined, these data identify Brm as a major effector of serum androgen-induced proliferation in the prostate that is disrupted in human disease, and indicate that loss of Brm confers a proliferative advantage in prostate cancer.
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PMID:The SWI/SNF ATPase Brm is a gatekeeper of proliferative control in prostate cancer. 1907 82

Androgen receptor (AR) plays a pivotal role in prostate cancer, primarily by regulating different gene expression programs elicited by androgen, which is important for cancer cell proliferation, survival, and differentiation. It is believed that the transcriptional function of AR is mediated largely by distinct nuclear coregulators. We report here the identification of ANCCA (also known as ATAD2), a new member of the AAA+ ATPase family proteins, as a novel AR coactivator. ANCCA interacts directly with AR and enhances its transcriptional activity, and is required for androgen-stimulated expression of a specific subgroup of genes including IGF1R, IRS-2, SGK1, and survivin. Upon androgen stimulation, ANCCA together with AR is recruited to the specific AR target genes. Suppression of ANCCA expression strongly inhibited the proliferation of androgen-responsive or androgen-independent, AR-positive prostate cancer cells and caused a significant increase of cellular apoptosis. Strikingly, the ANCCA gene itself, located at chromosome 8q24, is highly induced by androgen in androgen-dependent prostate cancer cells and xenograft tumors. Although ANCCA is hardly detected in normal human prostate tissue, high levels of ANCCA are found in hormone-independent prostate cancer cell lines, xenograft tumor, and a subset of prostate cancers with high Gleason scores. Together, these findings suggest that ANCCA plays an important role in prostate cancer by mediating specific AR functions in cancer cell survival and proliferation. The possession of ATPase and bromodomain by ANCCA makes it an attractive target for the development of therapeutics for the disease.
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PMID:Androgen-induced coactivator ANCCA mediates specific androgen receptor signaling in prostate cancer. 1931 66

Apoptotic effects of protocatechuic acid (PCA) at 1, 2, 4, 8 micromol/L on human breast cancer MCF7 cell, lung cancer A549 cell, HepG2 cell, cervix HeLa cell, and prostate cancer LNCaP cell were examined. Results showed that PCA concentration-dependently decreased cell viability, increased lactate dehydrogenase leakage, enhanced DNA fragmentation, reduced mitochondrial membrane potential, and lowered Na(+)-K(+)-ATPase activity for these cancer cells (P < 0.05). PCA also concentration-dependently elevated caspase-3 activity in five cancer cells (P < 0.05), but this agent at 2-8 micromol/L significantly increased caspase-8 activity (P < 0.05). PCA concentration-dependently decreased intercellular adhesion molecule level in test cancer cells (P < 0.05) but significantly inhibited cell adhesion at 2-8 micromol/L (P < 0.05). PCA also concentration-dependently lowered the levels of interleukin (IL)-6 and IL-8 in five cancer cells (P < 0.05), but this agent at 2-8 micromol/L significantly suppressed vascular endothelial growth factor production (P < 0.05). These findings suggest that PCA is a potent anticancer agent to cause apoptosis or retard invasion and metastasis in these five cancer cells.
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PMID:Apoptotic effects of protocatechuic acid in human breast, lung, liver, cervix, and prostate cancer cells: potential mechanisms of action. 1960 77

Analogues of the compound 2,5-di-tert-butylhydroquinone (BHQ) are capable of inhibiting the enzyme sarco/endoplasmic reticulum ATPase (SERCA) in the low micromolar and submicromolar concentration ranges. Not only are SERCA inhibitors valuable research tools, but they also have potential medicinal value as agents against prostate cancer. This study describes the synthesis of 13 compounds representing several classes of BHQ analogues, such as hydroquinones with a single aromatic substituent, symmetrically and unsymmetrically disubstituted hydroquinones, and hydroquinones with omega-amino acid tethers attached to their hydroxyl groups. Structure-activity relationships were established by measuring the inhibitory potencies of all synthesized compounds in bioassays. The assays were complemented by computational ligand docking for an analysis of the relevant ligand/receptor interactions.
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PMID:Design, synthesis, and biological evaluation of hydroquinone derivatives as novel inhibitors of the sarco/endoplasmic reticulum calcium ATPase. 1969 45

Prostate cancer possesses its unique feature of low proliferation rate and slow growth. Ca(2+)-induced apoptosis is not dependent on cell cycle progression and targeting this pathway could circumvent the problems encountered using current cytotoxic chemotherapies for prostate cancer. Hypoxia-inducible factor 1alpha (HIF-1alpha) is another novel cancer drug target and inhibitors of hypoxia-response pathway are being developed. Digoxin and other cardiac glycosides, known inhibitors of the alpha-subunit of sarcolemmal Na(+)K(+)-ATPase, were recently found to block tumor growth via the inhibition of HIF-1alpha synthesis. Thus, cardiac glycosides disrupt two important cellular pathways and, therefore, may be useful as an anticancer therapy. This review will focus on HIF-1alpha and calcium signaling as novel cancer drug targets in prostate cancer. The possible application of digoxin and other cardiac glycosides in cancer therapeutics especially in prostate cancer is discussed.
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PMID:HIF-1alpha and calcium signaling as targets for treatment of prostate cancer by cardiac glycosides. 2002 75

The SNF2-related CBP activator protein (SRCAP) serves as a coactivator for several nuclear receptors including the androgen receptor (AR). SRCAP is an ATPase that is the core subunit of a large multiprotein complex and was shown to incorporate the histone variant H2A.Z into nucleosomes. In this report, we demonstrate that SRCAP is expressed in the epithelium of normal prostate and in prostate carcinoma cells, and is associated with AR in the nucleus. Using transient transfection assays we demonstrate that SRCAP activates hormone-dependent transcription of the androgen responsive, prostate specific antigen (PSA)-Luciferase reporter gene in human prostate cells. The in vivo occupancy of SRCAP at the endogenous PSA promoter is demonstrated using chromatin immunoprecipitation assays. ShRNA mediated knockdown of SRCAP resulted in decreased H2A.Z binding at the enhancer region of the PSA promoter and decreased expression of PSA in prostate cancer cells. Furthermore, inhibition of SRCAP expression significantly inhibited androgen dependent prostate cancer cell growth. These data identify SRCAP as a physiologically relevant mediator of PSA expression, and demonstrate that SRCAP plays a role in prostate cancer cell proliferation.
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PMID:The chromatin remodeling factor SRCAP modulates expression of prostate specific antigen and cellular proliferation in prostate cancer cells. 2043 34

In order to investigate the clinical value of ATPase family AAA domain containing 3A (ATAD3A), a potential anti-apoptotic factor in prostate cancer (PCa), immunohistochemistry was used to measure ATAD3A expression in pathological specimens from 86 Chinese patients and in 183 tissue-array samples from American patients. The effect of ATAD3A on the expression of prostate specific antigen (PSA) and drug resistance in PCa cell lines was determined by in vitro experiments. ATAD3A was detected in 74 of 86 (86.0%) Chinese specimens and in 145 of 183 (79.2%) American patient samples. No difference was found in ATAD3A expression between these two patient groups. In vitro, silencing of ATAD3A expression reduced PSA secretion and cisplatin resistance, suggesting that ATAD3A was associated with PSA secretion and drug resistance in PCa.
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PMID:ATPase family AAA domain containing 3A is an anti-apoptotic factor and a secretion regulator of PSA in prostate cancer. 2158 87


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