Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.11.2 (prolyl hydroxylase)
 1,814 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Low oxygen tension-mediated transcription by hypoxia-inducible factors (HIF) has been reported to facilitate tumor progression, therapeutic resistance, and metastatic adaptation. One previously described target of hypoxia-mediated transcription is the cytokine/growth factor macrophage migration inhibitory factor (MIF). In studies designed to better understand hypoxia-stimulated MIF function, we have discovered that not only is MIF induced by hypoxia in pancreatic adenocarcinoma but MIF is also necessary for maximal hypoxia-induced HIF-1alpha expression. Cells lacking MIF are defective in hypoxia- and prolyl hydroxylase inhibitor-induced HIF-1alpha stabilization and subsequent transcription of glycolytic and angiogenic gene products. Moreover, COP9 signalosome subunit 5 (CSN5), a component of the COP9 signalosome previously reported to functionally interact with MIF, has recently been shown to interact with and stabilize HIF-1alpha. Our results indicate that MIF interacts with CSN5 in pancreatic cancer cells and that MIF-depleted cells display marked defects in hypoxia-induced CSN5/HIF-1alpha interactions. This functional interdependence between HIF-1alpha and MIF may represent an important and previously unrecognized pro-tumorigenic axis.
Cancer Res 2007 Jan 01
PMID:Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization. 1721 Jun 98

Angiogenesis requires the deposition of type IV collagen by endothelial cells into the basement membrane of new blood vessels. Stabilization of type IV collagen triple helix depends on the hydroxylation of proline, which is catalyzed by the iron-containing enzyme prolyl hydroxylase. This enzyme, in turn, requires ascorbic acid to maintain the enzyme-bound iron in its reduced state. We hypothesized that dietary ascorbic acid might be required for tumor angiogenesis and, therefore, tumor growth. Here, we show that, not surprisingly, ascorbic acid is necessary for the synthesis of collagen type IV by human endothelial cells and for their effective migration and tube formation on a basement membrane matrix. Furthermore, ascorbic acid depletion in mice incapable of synthesizing ascorbic acid (Gulo(-/-)) dramatically restricts the in vivo growth of implanted Lewis lung carcinoma tumors. Histopathological analyses of these tumors reveal poorly formed blood vessels, extensive hemorrhagic foci, and decreased collagen and von Willebrand factor expression. Our data indicate that ascorbic acid plays an essential role in tumor angiogenesis and growth, and that restriction of ascorbic acid or pharmacological inhibition of prolyl hydroxylase may prove to be novel therapeutic approaches to the treatment of cancer.
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PMID:Depletion of ascorbic acid restricts angiogenesis and retards tumor growth in a mouse model. 1732 43

The mitochondrial succinate dehydrogenase (SDH) is an essential component of the electron transport chain and of the tricarboxylic acid cycle. Also known as complex II, this tetrameric enzyme catalyzes the oxidation of succinate to fumarate and reduces ubiquinone. Mutations in the human SDHB, SDHC, and SDHD genes are tumorigenic, leading to the development of several types of tumors, including paraganglioma and pheochromocytoma. The mechanisms linking SDH mutations to oncogenesis are still unclear. In this work, we used the yeast SDH to investigate the molecular and catalytic effects of tumorigenic or related mutations. We mutated Arg(47) of the Sdh3p subunit to Cys, Glu, and Lys and Asp(88) of the Sdh4p subunit to Asn, Glu, and Lys. Both Arg(47) and Asp(88) are conserved residues, and Arg(47) is a known site of cancer causing mutations in humans. All of the mutants examined have reduced ubiquinone reductase activities. The SDH3 R47K, SDH4 D88E, and SDH4 D88N mutants are sensitive to hyperoxia and paraquat and have elevated rates of superoxide production in vitro and in vivo. We also observed the accumulation and secretion of succinate. Succinate can inhibit prolyl hydroxylase enzymes, which initiate a proliferative response through the activation of hypoxia-inducible factor 1alpha. We suggest that SDH mutations can promote tumor formation by contributing to both reactive oxygen species production and to a proliferative response normally induced by hypoxia via the accumulation of succinate.
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PMID:Ubiquinone-binding site mutations in the Saccharomyces cerevisiae succinate dehydrogenase generate superoxide and lead to the accumulation of succinate. 1763 59

Hypoxia occurs in cancer, prolonged exercise, and long-term ischemia with durations of several hours or more, and the hypoxia-inducible factor 1 (HIF1) pathway response to these conditions differs from responses to transient hypoxia. We used computational modeling, validated by experiments, to gain a quantitative, temporal understanding of the mechanisms driving HIF1 response. To test the hypothesis that HIF1 alpha protein levels during chronic hypoxia are tightly regulated by a series of molecular feedbacks, we took into account protein synthesis and product inhibition, and analyzed HIF1 system changes in response to hypoxic exposures beyond 3 to 4 h. We show how three autocrine feedback loops together regulate HIF 1 alpha hydroxylation in different microenvironments. Results demonstrate that prolyl hydroxylase, succinate and HIF1 alpha feedback determine intracellular HIF1 alpha levels over the course of hours to days. The model provides quantitative insight critical for characterizing molecular mechanisms underlying a cell's response to long-term hypoxia.
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PMID:Three autocrine feedback loops determine HIF1 alpha expression in chronic hypoxia. 1772 Feb 60

Angiogenesis is the formation of new blood vessels out of the preexisting vascular network and involves a sequence of events that are of key importance in a broad array of physiological and pathological processes. The growth of tumor and metastasis are dependent on the formation of new blood vessels. The present study therefore aims at evaluating the antiangiogenic effect of beta-carotene using in vivo and in vitro models. Male C57BL/6 mice as well as B16F-10 cells were used for the experimental study. The in vivo study includes the inhibitory effect of beta-carotene on the formation of tumor-directed capillaries. Rat aortic ring assay, human umbilical vein endothelial cell proliferation, migration, and tube formation are used for assessing the in vitro antiangiogenic effect of beta-carotene. The differential regulation of proinflammatory cytokines as well as the inhibitory effect of beta-carotene on the activation and nuclear translocation of transcription factors are also assessed. Beta-carotene treatment significantly reduces the number of tumor-directed capillaries accompanied by altered serum cytokine levels. Beta-carotene is able to inhibit proliferation, migration, and tube formation of endothelial cells. Beta-carotene treatment downregulates the expression of matrix metalloproteinase (MMP)-2, MMP-9, prolyl hydroxylase, and lysyl oxidase gene expression and upregulates the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. The study reveals that beta-carotene treatment could alter proinflammatory cytokine production and could inhibit the activation and nuclear translocation of p65, p50, c-Rel subunits of nuclear factor-kappa B, and other transcription factors such as c-fos, activated transcription factor-2, and cyclic adenosine monophosphate response element-binding protein in B16F-10 melanoma cells. These observations show that beta -carotene exerts its antiangiogenic effect by altering the cytokine profile and could inhibit the activation and nuclear translocation of transcription factors.
Integr Cancer Ther 2007 Sep
PMID:Beta-carotene inhibits tumor-specific angiogenesis by altering the cytokine profile and inhibits the nuclear translocation of transcription factors in B16F-10 melanoma cells. 1776 39

The antitumorigenic activity of antioxidants has been presumed to arise from their ability to squelch DNA damage and genomic instability mediated by reactive oxygen species (ROS). Here, we report that antioxidants inhibited three tumorigenic models in vivo. Inhibition of a MYC-dependent human B lymphoma model was unassociated with genomic instability but was linked to diminished hypoxia-inducible factor (HIF)-1 levels in a prolyl hydroxylase 2 and von Hippel-Lindau protein-dependent manner. Ectopic expression of an oxygen-independent, stabilized HIF-1 mutant rescued lymphoma xenografts from inhibition by two antioxidants: N-acetylcysteine and vitamin C. These findings challenge the paradigm that antioxidants diminish tumorigenesis primarily through decreasing DNA damage and mutations and provide significant support for a key antitumorigenic effect of diminishing HIF levels.
Cancer Cell 2007 Sep
PMID:HIF-dependent antitumorigenic effect of antioxidants in vivo. 1778 4

Hypoxia-inducible factor-1 (HIF-1) plays an important role in stress-responsive gene expression. Although primarily sensitive to hypoxia, HIF-1 signaling can be regulated by a number of stress factors including metabolic stress, growth factors and molecules present in the extracellular matrix (ECM). Degradation of ECM by metalloproteinases (MMP) is important for tumor progression, invasion and metastasis. ECM is predominantly collagen, and the imino acids (Pro and HyPro) comprise 25% of collagen residues. The final step in collagen degradation is catalyzed by prolidase, the obligate peptidase for imidodipeptides with Pro and HyPro in the carboxyl terminus. Defective wound healing in patients with inherited prolidase deficiency is associated with histologic features of angiopathy suggesting that prolidase may play a role in angiogenesis. Because HIF-1 alpha is central to angiogenesis, we considered that prolidase may modulate this pathway. To test this hypothesis, we made expression constructs of human prolidase and obtained stable transfectants in colorectal cancer cells (RKO). Overexpression of prolidase resulted in increased nuclear hypoxia inducible factor (HIF-1 alpha) levels and elevated expression of HIF-1-dependent gene products, vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1). The activation of HIF-1-dependent transcription was shown by prolidase-dependent activation of hypoxia response element (HRE)-luciferase expression. We used an oxygen-dependent degradation domain (ODD)-luciferase reporter construct as a surrogate for HIF-1 alpha as an in situ prolyl-hydroxylase assay. Since this reporter is degraded by VHL-dependent mechanisms, the increased levels of luciferase observed with prolidase expression reflected the decreased HIF-1 alpha prolyl hydroxylase activity. Additionally, the differential expression of prolidase in 2 breast cancer cell lines showed prolidase-dependent differences in HIF-1 alpha levels. These findings show that metabolism of imidodipeptides by prolidase plays a previously unrecognized role in angiogenic signaling.
Int J Cancer 2008 Mar 15
PMID:Extracellular matrix and HIF-1 signaling: the role of prolidase. 1799 10

Biophytum sensitivum is a traditional oriental herbal medicine that is known for its immunostimulatory and antitumor effects. Tumor metastasis is the most important cause of cancer death. Although B sensitivum was shown to inhibit metastasis, the mechanism underlying this action is not well understood. In the present report, the authors had studied the effect of B sensitivum on the invasion and motility of B16F-10 melanoma cells and investigate the regulatory effect on the expression of matrix metalloproteases (MMPs), prolyl hydoxylase, lysyl oxidase, nm23, extracellular signal-regulated kinase (ERK)-1, ERK-2, signal transducer and activator of transcription (STAT)-1, and proinflammatory cytokines in metastatic tumor-bearing lungs. B sensitivum inhibited the invasion and motility of B16F-10 cells in a dose-dependent manner. B sensitivum inhibited the expression of MMP-2 and MMP-9, whereas it activated STAT-1 expression in metastatic tumor-bearing lungs. Similarly, inhibition of prolyl hydroxylase, lysyl oxidase, ERK-1, ERK-2, and vascular endothelial growth factor (VEGF) expression but activation of nm23 by B sensitivum was observed in metastatic tumor-bearing lungs. B sensitivum treatment also downregulated the expression of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and granulocyte monocyte-colony stimulating factor in metastatic tumor-bearing lungs. In B16F-10 cells, B sensitivum also inhibited the production of proinflammatory cytokines. Overall, the results indicate that B sensitivum exhibits antimetastatic effects through the inhibition of invasion and motility. The results also suggest that MMPs, prolyl hydroxylase, lysyl oxidase, nm23, ERKs, VEGF, STAT, and proinflammatory cytokines are critical regulators of the B sensitivum-mediated antimetastatic effect.
Integr Cancer Ther 2008 Mar
PMID:Biophytum sensitivum (L.) DC inhibits tumor cell invasion and metastasis through a mechanism involving regulation of MMPs, prolyl hydroxylase, lysyl oxidase, nm23, ERK-1, ERK-2, STAT-1, and proinflammatory cytokine gene expression in metastatic lung tissue. 1829 94

Hypoxia exists in solid tumor tissues due to abnormal vasculature, vascular insufficiency, treatment or malignancy related anemia, and low intratumor blood flow. Hypoxic status in solid tumor promotes accumulation of hypoxia-inducible factor-1 alpha which is promptly degraded by proteasomal ubiquitination under normoxic conditions. However, under hypoxic conditions, the ubiquitination system for HIF-1 alpha is inhibited by inactivation of prolyl hydroxylase which is responsible for hydroxylation of proline in the oxygen-dependent degradation domain of HIF-1 alpha. HIF-1 alpha is an important transcriptional factor that codes for hundreds of genes involved in erythropoiesis, angiogenesis, induction of glycolytic enzymes in tumor tissues, modulation of cancer cell cycle, cancer proliferation, and cancer metastasis. Hypoxia and accumulation of HIF-1 alpha in solid tumor tissues have been reported to associate with resistance to chemotherapy, radiotherapy, and immunotherapy and poor prognosis. Production of vascular endothelial growth factor (VEGF) in cancer cells is regulated by the activated HIF-1 mediated system. An increase in VEGF levels subsequently induces HIF-1 alpha accumulation and promotes tumor metastasis by angiogenesis. Recently, angiogenesis targeting therapy using humanized VEGF antibody and VEGF receptor tyrosine kinase inhibitors have been used in solid cancer therapy. Nitric oxide (NO) is a unique chemical gaseous molecule that plays a role as a chemical messenger involved in vasodilator, neurotransmitter, and anti-platelet aggregation. In vivo, NO is produced and released from three different isoforms of NO synthase (NOS) and from exogenously administered NO donors. In cancer science, NO has been mainly discussed as an oncogenic molecule over the past decades. However, NO has recently been noted in cancer biology associated with cancer cell apoptosis, cancer cell cycle, cancer progression and metastasis, cancer angiogenesis, cancer chemoprevention, and modulator for chemo/radio/immuno-therapy. The presence and activities of all the three isoforms of NOS and were detected in cancer tissue components such as cancer cells, tumor-associated macrophages, and vascular endothelium. Overexpression of iNOS in cancer tissues has been reported to associate with poor prognosis in patients with cancers. On the other hand, NO donors such as nitroglycerin have been demonstrated to improve the effects of cancer therapy in solid cancers. Nitroglycerin has been used safely for a long time as a potent vasodilator for the treatment of ischemic heart diseases or heart failure. Therefore, we think highly of clinical use of nitroglycerin as a novel cancer therapy in combination with anticancer drugs for improvement of cancer therapeutic levels. In this review article, we demonstrate the unique physiological characteristics of malignant solid tumors, several factors in solid tumors resulting in resistance for cancer therapies, and the effects of NO from NOS or exogenous NO-donating drugs on malignant cells. Furthermore, we refer to promising therapeutic roles of NO and NO-donating drugs for novel treatments in solid tumors.
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PMID:Solid tumor physiology and hypoxia-induced chemo/radio-resistance: novel strategy for cancer therapy: nitric oxide donor as a therapeutic enhancer. 1850 79

Erythropoietin (Epo) is a peptide hormone that stimulates erythropoiesis. There are several agents in clinical use and in development that either act as ligands for the cell surface receptors of Epo or promote Epo production, which stimulates erythropoiesis. These are known as erythropoietic agents. The agents already in use include epoetin alfa, epoetin beta, and darbepoetin alfa. Newer agents under active investigation include continuous erythropoietin receptor activator (CERA) or proline hydroxylase inhibitors that increase hypoxia-inducible factor-1 (HIF-1), thereby stimulating Epo production and iron availability and supply. Erythropoietic agents have been shown to promote neuronal regeneration and to decrease post-stroke infarct size in mouse models. They have also been reported to shorten survival when used to treat anemia in many cancer patients and to increase thromboembolism. In contrast, rapid decrease of Epo levels as observed in astronauts and high-altitude dwellers upon rapid descent to sea level leads to the decrease of erythroid mass, a phenomenon known as "neocytolysis." The relative decrease in the serum Epo level is known to occur in some subjects with otherwise unexplained anemia of aging. Anemia by itself is a predictor of poor physical function in the elderly and is a significant economic burden on society. One out of every five persons in the United States will be elderly by 2050. Erythropoietic agents, by preventing and treating otherwise unexplained anemias of the elderly and anemia associated with other disease conditions of the elderly, have the potential to improve the functional capacity and to decrease the morbidity and mortality in the elderly, thereby alleviating the overall burden of medical care in society.
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PMID:Erythropoietic agents and the elderly. 1880 98


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