Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PAS transcription factor consisting of HIF-1 alpha and HIF-1 beta subunits. HIF-1 alpha expression and HIF-1 transcriptional activity increase exponentially as cellular O2 concentration is decreased. Several dozen target genes that are transactivated by HIF-1 have been identified, including those encoding erythropoietin, glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. The products of these genes either increase O2 delivery or allow metabolic adaptation to reduced O2 availability. HIF-1 is required for cardiac and vascular development and embryonic survival. In fetal and postnatal life, HIF-1 is required for a variety of physiological responses to chronic hypoxia. HIF-1 expression is increased in tumor cells by multiple mechanisms and may mediate adaptation to hypoxia that is critical for tumor progression. HIF-1 thus appears to function as a master regulator of O2 homeostasis that plays essential roles in cellular and systemic physiology, development, and pathophysiology.
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PMID:Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. 1061 72

Hypoxia-inducible factor 1 (HIF-1) controls oxygen delivery (via angiogenesis) and metabolic adaptation to hypoxia (via glycolysis). HIF-1 consists of a constitutively expressed HIF-1 beta subunit and an oxygen- and growth-factor-regulated HIF-1 alpha subunit. In xenografts, tumor growth and angiogenesis are correlated with HIF-1 expression. In human cancers, HIF-1 alpha is overexpressed as a result of intratumoral hypoxia and genetic alterations affecting key oncogenes and tumor suppressor genes. HIF-1 alpha overexpression in biopsies of brain, breast, cervical, esophageal, oropharyngeal and ovarian cancers is correlated with treatment failure and mortality. Increased HIF-1 activity promotes tumor progression, and inhibition of HIF-1 could represent a novel approach to cancer therapy.
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PMID:HIF-1 and tumor progression: pathophysiology and therapeutics. 1192 90

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1 alpha and HIF-1 beta/aryl hydrocarbon nuclear translocator subunits. HIF-1 expression is induced by hypoxia, growth factors, and activation of oncogenes. In response to hypoxia, HIF-1 activates the expression of many genes including vascular endothelial growth factor (VEGF) and erythropoietin. HIF-1 and VEGF play an important role in angiogenesis and tumor progression. Vanadate is widely used in industry, and is a potent inducer of tumors in humans and animals. In this study, we demonstrate that vanadate induces HIF-1 activity through the expression of HIF-1alpha but not HIF-1 beta subunit, and increases VEGF expression in DU145 human prostate carcinoma cells. We also studied the signaling pathway involved in vanadate-induced HIF-1 alpha and VEGF expression and found that phosphatidylinositol 3-kinase/Akt signaling was required for HIF-1 and VEGF expression induced by vanadate, whereas mitogen-activated protein kinase pathway was not required. We also found that reactive oxygen species (ROS) were involved in vanadate-induced expression of HIF-1 and VEGF in DU145 cells. The major species of ROS responsible for the induction of HIF-1 and VEGF expression was H(2)O(2). These results suggest that the expression of HIF-1 and VEGF induced by vanadate through PI3K/Akt may be an important signaling pathway in the vanadate-induced carcinogenesis, and ROS may play an important role.
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PMID:Vanadate-induced expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor through phosphatidylinositol 3-kinase/Akt pathway and reactive oxygen species. 1207 Jan 40

Hypoxia-inducible factor 1 (HIF-1) is a master regulator of the transcriptional response to oxygen deprivation. HIF-1 has been implicated in the regulation of genes involved in angiogenesis [e.g., vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase] and anaerobic metabolism (e.g., glycolytic enzymes). HIF-1 is essential for angiogenesis and is associated with tumor progression. In addition, overexpression of HIF-1 alpha has been demonstrated in many common human cancers. Therefore, HIF-1 is an attractive molecular target for development of novel cancer therapeutics. We have developed a cell-based high-throughput screen for the identification of small molecule inhibitors of the HIF-1 pathway. We have genetically engineered U251 human glioma cells to stably express a recombinant vector in which the luciferase reporter gene is under control of three copies of a canonical hypoxia-responsive element (U251-HRE). U251-HRE cells consistently expressed luciferase in a hypoxia- and HIF-1-dependent fashion. We now report the results of a pilot screen of the National Cancer Institute "Diversity Set," a collection of approximately 2000 compounds selected to represent the greater chemical diversity of the National Cancer Institute chemical repository. We found four compounds that specifically inhibited HIF-1-dependent induction of luciferase but not luciferase expression driven by a constitutive promoter. In addition, these compounds inhibited hypoxic induction of VEGF mRNA and protein expression in U251 cells. Interestingly, three compounds are closely related camptothecin analogues and topoisomerase (Topo)-I inhibitors. We show that concomitant with HIF-1 and VEGF inhibition, the activity of the Topo-I inhibitors tested is associated with induction of cyclooxygenase 2 mRNA expression. The luciferase-based high-throughput screen is a feasible tool for the identification of small molecule inhibitors of HIF-1 transcriptional activation. In addition, our results suggest that altered Topo-I function may be associated with repression of HIF-1-dependent induction of gene expression.
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PMID:Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. 1215 35

Using human and rodent cells in vitro, we characterized a hypoxia-inducible signaling pathway as one of the pathways affected by carcinogenic nickel compounds. Acute exposure to nickel activates hypoxia-inducible transcription factor-1 (HIF-1), which strongly induces hypoxia-inducible genes, including the recently discovered tumor marker Cap43. This gene has been cloned based on its nickel inducibility and was found to be highly inducible by hypoxia. To identify other HIF-1-dependent/independent nickel-inducible genes, we used cells obtained from HIF-1 alpha null mouse embryos and analyzed gene expression changes using the microarray technique. We found that genes coding for glycolytic enzymes, known to be regulated by HIF-1, were also induced in nickel-exposed cells. In addition, we identified a number of new genes highly induced by nickel in an HIF-dependent manner. Elevated HIF-1 activity after acute nickel exposure might be selectively advantageous because nickel-transformed rodent and human cells possess increased HIF-1 transcriptional activity. Hypoxia plays an important role in tumor progression. It selects for cells with enhanced glycolytic activity, causing production of large amounts of lactic acid, one of the most common features of tumor cells (Warburg effect). Here, we hypothesize that exposure to nickel activates the hypoxia-inducible pathway and facilitates selection of cells with increased transcriptional activity of hypoxia-inducible genes, which may be important in the nickel-induced carcinogenic process.
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PMID:The role of hypoxia-inducible signaling pathway in nickel carcinogenesis. 1242 41

The hypoxia-inducible factors 1alpha (HIF-1alpha) and 2alpha (HIF-2alpha) have extensive structural homology and have been identified as transcription factors that mediate hypoxia-inducible gene expression through hypoxia-responsive element (HRE). They play critical roles not only in normal development, but also in tumor progression. Endothelial cells (EC) express both HIF-1alpha and -2alpha. In this study, we examined the subcellular localization of HIF-1alpha and -2alpha in bovine arterial EC (BAEC) by immunoblotting and immunocytostaining analysis and found that even under normoxic conditions, as with its heterodimeric partner ARNT, HIF-2alpha was stable, and was localized in the nucleus of BAEC differently than HIF-1alpha. HIF-2alpha might be regulated by a different mechanism than HIF-1alpha and might mediate the expression of some EC-specific genes under normoxic conditions. We further found that cardiovascular helix-loop-helix factor (CHF) 2, which had been identified as an ARNT-interacting protein, was expressed in BAEC and suppressed HRE-dependent gene expression both under normoxia and hypoxia. CHF2 might be one of the key regulators of HIF-2alpha-mediated gene expression in normoxic EC.
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PMID:Subcellular localization and regulation of hypoxia-inducible factor-2alpha in vascular endothelial cells. 1504 51

Hypoxia is a critical event in tumor progression and angiogenesis. Hypoxia can be detected noninvasively by a novel spectroscopic photoacoustic tomography technology (SPAT) and this finding is supported by our molecular biology investigation aimed to elucidate the etiopathogenesis of SPAT detected hypoxia and angiogenesis. The present study provides an integrated approach to define oxygen status (hypoxia) of intracranial tumor xenografts using spectroscopic photoacoustic tomography. Brain tumors can be identified based on their distorted vascular architecture and oxygen saturation (SO2) images. Noninvasive in vivo tumor oxygenation imaging using SPAT is based on the spectroscopic absorption differences between oxyhemoglobin (O2Hb) and deoxyhemoblobin (HHb). Sprague-Dawley rats inoculated intracranially with ENU1564, a carcinogen-induced rat mammary adenocarcinoma cell line, were imaged with SPAT three weeks post inoculation. Proteins important for tumor angiogenesis and invasion were detected in hypoxic brain foci identified by SPAT and were elevated compared with control brain. Immunohistochemistry, Western blotting, and semi-quantitative RT-PCR showed that HIF-1 alpha, VEGF-A, and VEGFR2 (Flk-1) protein and mRNA expression levels were significantly higher (P < 0.05) in brain tumor tissues compared to normal brain. Gelatin zymography and RT-PCR demonstrated the upregulation of MMP-9 in tumor foci compared with brain control. Together these results suggest the critical role of hypoxia in driving tumor angiogenesis and invasion through upregulation of target genes important for these functions. Moreover this report validates our hypothesis that a novel noninvasive technology (SPAT) developed in our laboratory is suitable for detection of tumors, hypoxia, and angiogenesis.
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PMID:In vivo imaging and characterization of hypoxia-induced neovascularization and tumor invasion. 1714 11

Tumor growth and metastasis are dependent on angiogenesis, and endothelial cell invasion and migration are apparent means of regulating tumor progression. We report here that saxatilin, a snake venom-derived disintegrin, suppresses the angiogenesis-inducing properties of NCI-H460 human lung cancer cells. Culture supernatants of NCI-H460 cells are able to induce human umbilical vascular endothelial cell (HUVEC) invasion and tube formation. However, treatment of the cancer cells with saxatilin resulted in reduced angiogenic activity of the culture supernatant. This suppressed angiogenic property was found to be associated with the level of vascular endothelial growth factor (VEGF) in the culture supernatant. Further experimental evidence indicated that saxatilin inhibits VEGF production in NCI-H460 cells by affecting hypoxia induced factor-1 alpha (HIF-1 alpha) expression via the Akt pathway.
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PMID:Saxatilin suppresses tumor-induced angiogenesis by regulating VEGF expression in NCI-H460 human lung cancer cells. 1756 97

N-myc downstream-regulated gene 1 (NDRG1) is an intracellular protein that is induced under a wide variety of stress and cell growth-regulatory conditions. NDRG1 is up-regulated by cell differentiation signals in various cancer cell lines and suppresses tumor metastasis. Despite its specific role in the molecular cause of Charcot-Marie-Tooth type 4D disease, there has been more interest in the gene as a marker of tumor progression and enhancer of cellular differentiation. Because it is strongly up-regulated under hypoxic conditions, and this condition is prevalent in solid tumors, its regulation is somewhat complex, governed by hypoxia-inducible factor 1 alpha (HIF-1alpha)- and p53-dependent pathways, as well as its namesake, neuroblastoma-derived myelocytomatosis, and probably many other factors, at the transcriptional and translational levels, and through mRNA stability. We survey the data for clues to the NDRG1 gene's mechanism and for indications that the NDRG1 gene may be an efficient diagnostic tool and therapy in many types of cancers.
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PMID:NDRG1, a growth and cancer related gene: regulation of gene expression and function in normal and disease states. 1791 2

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.
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PMID:Extracellular matrix and HIF-1 signaling: the role of prolidase. 1799 10


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