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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of haloperidol and propranolol on aggressiveness, motility exploration and general behavior, and the activity or level of adenylate cyclase, cyclic AMP, and protein kinase in the brain of mice treated with LSD was tested. Haloperidol evidently, and propranolol slightly less, inhibited the behavioral and biochemical changes induced by LSD. It is suggested that psychotomimetic effects of LSD depend on complex action of this compound on aminergic receptors in the central nervous system, and the antipsychotic effectiveness of haloperidol and propranolol is related to interaction of these drugs and LSD with the receptors for monoamines participating in the central neuromediation.
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PMID:The influence of haloperidol and propranolol on behavior and biochemical changes in the brain of mice treated with LSD. 19 69

Dysregulation of enzymes involved in prostaglandin biosynthesis plays a critical role in influencing the biological behavior and clinical outcome of several tumors. In human gliomas, overexpression of cyclooxygenase-2 has been linked to increased aggressiveness and poor prognosis. In contrast, the role of prostaglandin E synthase in influencing the biological behavior of human gliomas has not been established. We report that constitutive expression of the microsomal prostaglandin E synthase-1 (mPGES-1) is associated with increased prostaglandin E(2) (PGE(2)) production and stimulation of growth in the human astroglioma cell line U87-MG compared with human primary astrocytes. Consistently, pharmacologic and genetic inhibition of mPGES-1 activity and expression blocked the release of PGE(2) from U87-MG cells and decreased their proliferation. Conversely, exogenous PGE(2) partially overcame the antiproliferative effects of mPGES-1 inhibition and stimulated U87-MG cell proliferation in the absence of mPGES-1 inhibitors. The EP2/EP4 subtype PGE(2) receptors, which are linked to stimulation of adenylate cyclase, were expressed in U87-MG cells to a greater extent than in human astrocytes. PGE(2) increased cyclic AMP levels and stimulated protein kinase A (PKA) activity in U87-MG cells. Treatment with a selective type II PKA inhibitor decreased PGE(2)-induced U87-MG cell proliferation, whereas a selective type I PKA inhibitor had no effect. Taken together, these results are consistent with the hypothesis that mPGES-1 plays a critical role in promoting astroglioma cell growth via PGE(2)-dependent activation of type II PKA.
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PMID:Microsomal prostaglandin E synthase-1 regulates human glioma cell growth via prostaglandin E(2)-dependent activation of type II protein kinase A. 1689 68

Pancreatic cancer has the worst prognosis among cancers due to the difficulty of early diagnosis and its aggressive behavior. To characterize the aggressiveness of pancreatic cancers on gene expression, pancreatic cancer xenografts transplanted into severe combined immunodeficient mice served as a panel for gene-expression profiling. As a result of profiling, the adenylate cyclase-associated protein 1 (CAP1) gene was shown to be overexpressed in all of the xenografts. The expression of CAP1 protein in all 73 cases of pancreatic cancer was recognized by immunohistochemical analyses. The ratio of CAP1-positive tumor cells in clinical specimens was correlated with the presence of lymph node metastasis and neural invasion, and also with the poor prognosis of patients. Immunocytochemical analyses in pancreatic cancer cells demonstrated that CAP1 colocalized to the leading edge of lamellipodia with actin. Knockdown of CAP1 by RNA interference resulted in the reduction of lamellipodium formation, motility, and invasion of pancreatic cancer cells. This is the first report demonstrating the overexpression of CAP1 in pancreatic cancers and suggesting the involvement of CAP1 in the aggressive behavior of pancreatic cancer cells.
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PMID:Adenylate cyclase-associated protein 1 overexpressed in pancreatic cancers is involved in cancer cell motility. 1918 11

Osteosarcoma is the most common malignant primary bone tumor in children and adolescents. The clinical outcome for osteosarcoma remains discouraging despite aggressive surgery and intensive radiotherapy and chemotherapy regimens. Thus, novel therapeutic approaches are needed. Previously, we have shown that inorganic phosphate (Pi) inhibits proliferation and aggressiveness of human osteosarcoma U2OS cells identifying adenylate cyclase, beta3 integrin, Rap1, ERK1/2 as proteins whose expression and function are relevantly affected in response to Pi. In this study, we investigated whether Pi could affect chemosensitivity of osteosarcoma cells and the underlying molecular mechanisms. Here, we report that Pi inhibits proliferation of p53-wild type U2OS cells (and not of p53-null Saos and p53-mutant MG63 cells) by slowing-down cell cycle progression, without apoptosis occurrence. Interestingly, we found that Pi strongly enhances doxorubicin-induced cytotoxicity in U2OS, and not in Saos and MG63 cells, by apoptosis induction, as revealed by a marked increase of sub-G1 population, Bcl-2 downregulation, caspase-3 activation, and PARP cleavage. Remarkably, Pi/doxorubicin combination-induced cytotoxicity was accompanied by an increase of p53 protein levels and of p53 target genes mdm2, p21 and Bax, and was significantly reduced by the p53 inhibitor pifithrine-alpha. Moreover, the doxorubicin-induced cytotoxicity was associated with ERK1/2 pathway inhibition in response to Pi. Altogether, our data enforce the evidence of Pi as a novel signaling molecule capable of inhibiting ERK pathway and inducing sensitization to doxorubicin of osteosarcoma cells by p53-dependent apoptosis, implying that targeting Pi levels might represent a rational strategy for improving osteosarcoma therapy.
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PMID:Inorganic phosphate enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin via a p53-dependent pathway. 2267 30

Inorganic phosphate (Pi) is an essential nutrient to living organisms. It plays a key role in diverse biological processes, including osteoblast differentiation and skeletal mineralization. Maintenance of proper Pi homeostasis is a critical event, as any deviation from that state can lead to several acute and chronic disease states and influence the ageing process and lifespan. Serum Pi level is maintained within a narrow range through a complex interplay between intestinal absorption, exchange with intracellular and bone storage pools, renal tubular reabsorption and depends mainly on the activity of Na/Pi cotransporters. Pi is abundant in the diet and intestinal absorption of Pi is efficient and minimally regulated. The kidney is a major regulator of Pi homeostasis and can increase or decrease its Pi reabsorptive capacity to accommodate Pi need. Relevantly, Pi is emerging as an important signalling molecule capable of modulating multiple cellular functions by altering signal transduction pathways, gene expression and protein abundance in many cell types. However, little is known about the initial events involving the detection of changes in serum or local Pi concentrations and the subsequent downstream regulation cascade. Previously, we provided evidence that Pi inhibits proliferation and aggressiveness of human osteosarcoma U2OS cells identifying adenylate cyclase, beta3 integrin, Rap1, ERK1/2 as proteins whose expression and function are relevantly affected in response to Pi. More recently, we demonstrated that Pi is capable also of inducing sensitization of osteosarcoma cells to doxorubicin in a p53-dependent manner and through a mechanism involving ERK1/2 down-regulation. This review summarizes the current knowledge regarding inorganic phosphate as a novel specific signaling molecule in bone and other cell types in mammals and discuss how targeting Pi levels at local sites might represent a potential strategy for improving osteosarcoma therapy.
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PMID:Inorganic phosphate as a signaling molecule: a potential strategy in osteosarcoma treatment. 2339 88

An established inverse clinical correlation between serum adiponectin levels and renal cell carcinoma (RCC) aggressiveness exists. We have recently demonstrated that adiponectin suppresses clear cell RCC (ccRCC) progression through interaction with its receptor, adiponectin receptor 1 (AdipoR1). ERp46 has been shown to inhibit adiponectin signaling via interaction with AdipoR1 in HeLa cells. However, the expression of ERp46 in RCC has not been described thus far. The objectives of this study were to investigate ERp46 in RCC, its expression, its effects on RCC growth in a mouse model and whether it interacts with AdipoR1. We demonstrated a higher ERp46/AdipoR1 expression ratio in metastatic compared to non-metastatic ccRCC, as determined by immunohistochemistry of tissue microarrays and subsequent image analysis. When ERp46 was stably knocked down using shRNA or overexpressed in murine RCC RAG cells, RCC growth after subcutaneous injection in BALB/c nude mice was inhibited and accelerated, respectively. In vitro analysis to determine the molecular interaction between AdipoR1 and ERp46 included co-immunoprecipitation using human ccRCC 786-O cells and a bacterial adenylate cyclase-based two hybrid system and demonstrated no sustained AdipoR1-ERp46 interaction. This is the first report to suggest a role for ERp46 as a potential therapeutic target in RCC given its expression profile in human RCC samples and its effect on in vivo RCC growth. Since a stable interaction with AdipoR1 could not be established, we suggest that the tumorigenic properties of ERp46 in RCC cells are not related to an inhibitory modulation of AdipoR1.
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PMID:Endoplasmic reticulum protein ERp46 in renal cell carcinoma. 2459 73

In many common cancers, production of cAMP boosts cancer proliferation, survival, and aggressiveness, reflecting the fact that, through mechanisms that require further clarification, cAMP can promote tyrosine phosphorylation, notably transactivation of the epidermal growth factor receptor (EGFR). Hormones which activate adenylate cyclase in many cancers include PGE2 - often produced by cox-2 activity within tumors - and adrenergic hormones, acting on beta2 receptors. NSAID cyclooxygenase inhibitors, including low-dose aspirin, clearly reduce risk for many adenocarcinomas, but the impact of cox-2 inhibitors in clinical cancer therapy remains somewhat equivocal. There is increasing evidence that increased sympathetic drive, often reflecting psychic stress or tobacco usage, increases risk for, and promotes the aggressiveness of, many cancers. The non-specific beta antagonist propranolol shows cancer-retardant activity in pre-clinical rodent studies, especially in stressed animals, and a limited amount of epidemiology concludes that concurrent propranolol usage is associated with superior prognosis in breast cancer, ovarian cancer, and melanoma. Epidemiology correlating increased resting heart rate with increased total cancer mortality can be interpreted as compelling evidence that increased sympathetic drive encourages the onset and progression of common cancers. Conversely, hormones which inhibit adenylate cyclase activity in cancers may have potential for cancer control; GABA, which can be administered as a well-tolerated nutraceutical, has potential in this regard. Combination regimens intended to down-regulate cancer cAMP levels, perhaps used in conjunction with EGFR inhibitors, may have considerable potential for suppressing the contribution of cAMP/EGFR to cancer aggressiveness. This model also predicts that certain other hormones which activate adenylate cylase in various tissue may play a yet-unsuspected role in cancer induction and spread.
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PMID:A role for cAMP-driven transactivation of EGFR in cancer aggressiveness - therapeutic implications. 2493 79

Melanocyte development and differentiation are regulated by cAMP, which is produced by the adenylate cyclase (AC) enzyme upon activation of the melanocortin-1-receptor (MC1R). Individuals carrying single amino acid substitution variants of MC1R have impaired cAMP signaling and higher risk of melanoma. However, the contribution of AC to this risk is not clear. Downstream of AC, the phosphorylated transcription factor, cyclic AMP Responsive Element Binding Protein (pCREB), which is activated by protein kinase A, regulates the expression of several genes including the melanocyte master regulator MITF. The roles of AC and CREB in melanoma development and growth are not well understood. Here, we investigated the effect of topical application of AC inhibitor on Braf^CA/Pten^-/- mouse melanoma development. We show that AC inhibitor delays melanoma growth independent of MAPK pathway activity and melanin content. Next, employing a primary melanoma tissue microarray and quantitative immunohistochemistry, we show that pCREB levels are positively correlated with the proliferative status of melanoma, but low pCREB expression is associated with tumor aggressiveness and metastatic recurrence. These data suggest that low cAMP signaling inhibits tumor growth but is a predictor of melanoma aggressiveness.
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PMID:Elevated cyclic AMP levels promote BRAF^CA/Pten^-/- mouse melanoma growth but pCREB is negatively correlated with human melanoma progression. 2917 97

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