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James F. Riordan - One of the best experts on this subject based on the ideXlab platform.
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The nuclear function of Angiogenin in endothelial cells is related to rRNA production.
Biochemical and biophysical research communications, 2002Co-Authors: Takanori Tsuji, James F. RiordanAbstract:Angiogenin is a potent angiogenic protein whose inhibition is known to prevent human tumor growth in athymic mice. It is secreted by both tumor and normal cells; and interacts with endothelial and smooth muscle cells to induce a wide range of cellular responses including cell migration and invasion, proliferation, and formation of tubular structures. Angiogenin is rapidly endocytosed and translocated to the cell nucleus where it accumulates in the nucleolus and binds to DNA. Although nuclear translocation is necessary for its angiogenic activity, the nuclear function of Angiogenin is unclear. Here we report that exogenous Angiogenin enhances the production of 45S rRNA in endothelial cells, and reduction of endogenous Angiogenin inhibits its transcription. In a nuclear run-on assay, Angiogenin stimulates RNA synthesis including that containing the initiation site sequences of 45S rRNA. This suggests that the nuclear function of Angiogenin relates to its capacity to induce rRNA synthesis. Because rRNA transcription is essential for the synthesis of new ribosomes that are necessary for protein translation and cell growth, inhibition of Angiogenin-stimulated transcription of rRNA may inhibit angiogenesis and therefore, would serve as a molecular target for therapeutic intervention.
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Angiogenin activates erk1 2 in human umbilical vein endothelial cells
Biochemical and Biophysical Research Communications, 2001Co-Authors: Shumei Liu, James F. RiordanAbstract:Abstract Angiogenin is a potent angiogenic factor that binds to endothelial cells and is endocytosed and rapidly translocated to the nucleus where it is concentrated in the nucleolus and binds to DNA. Angiogenin also activates cell-associated proteases, induces cell invasion and migration, stimulates cell proliferation, and organizes cultured cells to form tubular structures. The intracellular signaling pathways that mediate these various cellular responses are not well understood. Here we report that Angiogenin induces transient phosphorylation of extracellular signal-related kinase1/2 (Erk1/2) in cultured human umbilical vein endothelial cells. Angiogenin does not affect the phosphorylation status of stress-associated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 mitogen-activated protein (MAP) kinases. PD98059—a specific inhibitor of MAP or Erk kinase 1 (MEK 1), the upstream kinase that phosphorylates Erk1/2—abolishes Angiogenin-induced Erk phosphorylation and cell proliferation without affecting nuclear translocation of Angiogenin. In contrast, neomycin, a known inhibitor of nuclear translocation and cell proliferation, does not interfere with Angiogenin-induced Erk1/2 phosphorylation. These data indicate that both intracellular signaling pathways and direct nuclear functions of Angiogenin are required for Angiogenin-induced cell proliferation and angiogenesis.
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Inhibition of human Angiogenin by DNA aptamers: nuclear colocalization of an Angiogenin-inhibitor complex.
Biochemistry, 1998Co-Authors: Valentina Nobile, Nello Russo, James F. RiordanAbstract:Specific ligands (aptamers) for Angiogenin were selected from a 72-mer oligodeoxynucleotide library consisting of 28 randomized positions flanked by two constant regions of 22 residues each. From a starting pool of approximately 10(14) molecules, 19 Angiogenin-binding ligands were obtained. Among them, two oligonucleotides showed significant inhibition of the ribonucleolytic activity of Angiogenin with apparent Kis of 0.65 and 0.60 micro M, respectively. One of them was shortened on the basis of its secondary structure to provide a 45-mer oligonucleotide that retained much of the inhibitory properties of the parent molecule. It inhibits both the angiogenic and cell proliferative activities of Angiogenin but does not interfere with its nuclear translocation in human endothelial cells. Importantly, the inhibitor is cotranslocated to the nucleus with Angiogenin in a approximately 1:1 stoichiometric ratio. These results demonstrate that the inhibition of Angiogenin-induced cell proliferation and angiogenesis by the oligonucleotide is due to suppression of the ribonucleolytic activity of Angiogenin, an event that occurs most likely within the cell nucleus.
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A putative Angiogenin receptor in Angiogenin-responsive human endothelial cells
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: James F. Riordan, Bert L ValleeAbstract:Angiogenin stimulates both [3H]thymidine incorporation and proliferation of human endothelial cells in sparse cultures. Under these conditions, a 170-kDa cell surface protein can be detected that binds Angiogenin specifically. Angiogenin-stimulated cell growth is concentration-dependent and is completely inhibited by an anti-Angiogenin monoclonal antibody, but not by a nonimmune control antibody. It is not affected by the nonangiogenic homolog, RNase A, nor by other angiogenic proteins, such as basic fibroblast growth factor and its antibody. Results suggest that under specific conditions, endothelial cells express an Angiogenin receptor that may mediate Angiogenin-stimulated DNA synthesis and proliferation and play an important role in Angiogenin-induced angiogenesis.
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Structure and Function of Angiogenin
Ribonucleases, 1997Co-Authors: James F. RiordanAbstract:Publisher Summary This chapter focuses on structure and functions of Angiogenin. In many ways, Angiogenin is the most unusual member of the ribonuclease superfamily. It shares 33% sequence identity with bovine pancreatic RNase A and has structurally equivalent counterparts for the two histidines and one lysine that comprise the catalytic residues for ribonucleolytic activity. It cleaves preferentially on the 3′ side of pyrimidines to generate a cyclic phosphate product that is subsequently hydrolyzed, but it is 4–6 orders of magnitude less active in routine assays. Despite such seemingly minuscule potency, this ribonucleolytic activity is absolutely critical to the biological function of Angiogenin. This chapter discusses in depth about angiogenesis and angiogenic molecules, human Angiogenin, and bovine Angiogenin. Characterization as a member of the ribonuclease family is explained. The chapter also elaborates the relationship of RNase activity and angiogenic activity. The chapter discusses about binding to endothelial cells, induction of second messengers, and effect on endothelial cell growth. The chapter concludes with a discussion on antiAngiogenin antibody suppression of tumor growth.
Josette Badet - One of the best experts on this subject based on the ideXlab platform.
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Angiogenin distribution in human term placenta, and expression by cultured trophoblastic cells.
Angiogenesis, 2003Co-Authors: Nadine Pavlov, Jean-louis Frendo, Elissavet Hatzi, Yann Bassaglia, Danièle Evain-brion, Josette BadetAbstract:Human Angiogenin is a 14-kDa secreted protein with angiogenic and ribonucleolytic activities. Angiogenin is associated with tumour development but is also present in normal biological fluids and tissues. To further address the physiological role of Angiogenin, we studied its expression in situ and in vitro, using the human term placenta as a model of physiological angiogenesis. Angiogenin was immunodetected by light and transmission electron microscopy, and its cellular distribution was established by double immunolabelling with cell markers including von Willebrand factor, platelet/endothelial cell adhesion molecule-1 (PECAM-1), CD34, Tie-2, vascular endothelial cadherin (VE-cadherin), vascular endothelial growth factor receptor-2 (VEGF-R2), erythropoeitin receptor (Epo-R), alpha-smooth muscle actin, CD45, cytokeratin 7, and Ki-67. Angiogenin immunoreactivity was detected in villous and extravillous trophoblasts, the trophoblast basement membrane, the endothelial basal lamina, foetal blood vessels, foetal and maternal red blood cells, and amnionic cells. Its expression was confirmed by in situ hybridisation with a digoxygenin-labelled cDNA probe and reverse transcriptase-polymerase chain reaction amplification. Villous cytotrophoblasts, isolated and differentiated in vitro into a functional syncytiotrophoblast, expressed and secreted Angiogenin. Given its known biological activities in vitro and its observed pattern of expression, these data suggest that, in human placenta, Angiogenin has a role not only in angiogenesis but also in vascular and tissue homeostasis, maternal immune tolerance of the foetus, and host defences.
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Angiogenin
2000Co-Authors: Josette BadetAbstract:Angiogenin is a plasma protein with angiogenic and ribonucleolytic activities. It is the first angiogenic protein to be isolated and characterised from conditioned medium of human tumour cells. This chapter reviews the structural, biochemical and biological properties of Angiogenin, its role in vascular biology, and its clinical relevance and potential therapeutic implications.
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Internalization and Processing of Human Angiogenin by Cultured Aortic Smooth Muscle Cells
Biochemical and Biophysical Research Communications, 2000Co-Authors: Elissavet Hatzi, Yann Bassaglia, Josette BadetAbstract:Human Angiogenin is a 14-kDa plasma protein with angiogenic and ribonucleolytic activities. Angiogenin binds specifically to aortic smooth muscle cells, activates second messenger pathways, and inhibits their proliferation. Human and bovine aortic smooth muscle cells were used to study the internalization and intracellular fate of human Angiogenin at 37°C. Using a specific antibody against Angiogenin, we found that the internalized native protein was localized in the perinuclear region at 30 min and then dispersed throughout the cytoplasm. In conditions favoring receptor-mediated endocytosis, internalization of iodinated Angiogenin showed a first peak at 5 min and then further increased for up to 24 h. The half-life of the molecule, calculated as 12 h in chase experiments, could contribute to its intracellular accumulation. In cell extracts, in addition to the 14-kDa protein, a 8.7-kDa fragment was observed at 24 h, and three fragments with molecular mass of 10.5, 8.7, and 6.1 kDa were detected at 48 h. Our data point to a specific internalization and processing of human Angiogenin by aortic smooth muscle cells.
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Expression of receptors for human Angiogenin in vascular smooth muscle cells
European Journal of Biochemistry, 1999Co-Authors: Elissavet Hatzi, Josette BadetAbstract:Human Angiogenin is a plasma protein with angiogenic and ribonucleolytic activities. Angiogenin inhibited both DNA replication and proliferation of aortic smooth muscle cells. Binding of 125I-Angiogenin to bovine aortic smooth muscle cells at 4 degrees C was specific, saturable, reversible and involved two families of interactions. High-affinity binding sites with an apparent dissociation constant of 0.2 nm bound 1 x 104 molecules per cell grown at a density of 3 x 104.cm-2. Low-affinity binding sites with an apparent dissociation constant of 0.1 micrometer bound 4 x 106 molecules.cell-1. High-affinity binding sites decreased as cell density increased and were not detected at confluence. 125I-Angiogenin bound specifically to cells routinely grown in serum-free conditions, indicating that the Angiogenin-binding components were cell-derived. Affinity labelling of sparse bovine smooth muscle cells yielded seven major specific complexes of 45, 52, 70, 87, 98, 210 and 250-260 kDa. The same pattern was obtained with human cells. Potential modulators of angiogenesis such as protamine, heparin and the placental ribonuclease inhibitor competed for Angiogenin binding to the cells. Together these data suggest that cultured bovine and human aortic smooth muscle cells express specific receptors for human Angiogenin.
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Angiogenin and endothelial cells
Experientia Supplementum, 1992Co-Authors: Josette Badet, Fabrice Soncin, Denis BarritaultAbstract:Antiogenin is a potent blood vessel-inducing polypeptide that has a unique ribonucleolytic activity. Initially identified from tumor cells conditioned medium through its ability to induce neovascularization in the chick embryo chorioallantoic membrane assay, Angiogenin has also been purified from normal plasma which suggested that it might be involved in endothelium homeostasis. Angiogenin is highly homologous to pancreatic ribonuclease A with 68% amino acid sequence homology and conserved essential active site residues [3]. However, Angiogenin is inactive in standard ribonuclease assays but has a ribonucleolytic specificity toward ribosomal and transfer RNAs. This enzymic activity might be relevant to the process of angiogenesis since a functional active site seems necessary for the expression of its angiogenic property; however, it appears not to be sufficient
Bert L Vallee - One of the best experts on this subject based on the ideXlab platform.
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An Angiogenic Protein from Bovine Serum and Milk — Purification and Primary Structure of Angiogenin-2
FEBS Journal, 1997Co-Authors: Daniel J. Strydom, Michael D Bond, Bert L ValleeAbstract:Bovine serum and milk contain a basic angiogenic protein that binds tightly to placental ribonuclease inhibitor. It was purified from both sources by ion-exchange and reversed-phase chromatographies. Its amino acid sequence revealed that it is a member of the ribonuclease superfamily. It contains 123 amino acids in a single polypeptide chain, is cross-linked by three disulfide bonds, is glycosylated at Asn33, and is 57% identical to bovine Angiogenin. The amino-terminal and carboxyl terminal residues are pyroglutamic acid and proline, respectively. The protein has ribonucleolytic activity that is similar to, but somewhat lower than, that of bovine Angiogenin, i.e. very low relative to RNase. It is angiogenically potent on chicken chorioallantoic membrane, but less so than Angiogenin. The sequence and activities demonstrate that this protein is a second, distinct, member of the Angiogenin sub-family of pancreatic ribonucleases, and is referred to as Angiogenin-2.
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an angiogenic protein from bovine serum and milk purification and primary structure of Angiogenin 2
FEBS Journal, 1997Co-Authors: Daniel J. Strydom, Michael D Bond, Bert L ValleeAbstract:Bovine serum and milk contain a basic angiogenic protein that binds tightly to placental ribonuclease inhibitor. It was purified from both sources by ion-exchange and reversed-phase chromatographies. Its amino acid sequence revealed that it is a member of the ribonuclease superfamily. It contains 123 amino acids in a single polypeptide chain, is cross-linked by three disulfide bonds, is glycosylated at Asn33, and is 57% identical to bovine Angiogenin. The amino-terminal and carboxyl terminal residues are pyroglutamic acid and proline, respectively. The protein has ribonucleolytic activity that is similar to, but somewhat lower than, that of bovine Angiogenin, i.e. very low relative to RNase. It is angiogenically potent on chicken chorioallantoic membrane, but less so than Angiogenin. The sequence and activities demonstrate that this protein is a second, distinct, member of the Angiogenin sub-family of pancreatic ribonucleases, and is referred to as Angiogenin-2.
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A putative Angiogenin receptor in Angiogenin-responsive human endothelial cells
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: James F. Riordan, Bert L ValleeAbstract:Angiogenin stimulates both [3H]thymidine incorporation and proliferation of human endothelial cells in sparse cultures. Under these conditions, a 170-kDa cell surface protein can be detected that binds Angiogenin specifically. Angiogenin-stimulated cell growth is concentration-dependent and is completely inhibited by an anti-Angiogenin monoclonal antibody, but not by a nonimmune control antibody. It is not affected by the nonangiogenic homolog, RNase A, nor by other angiogenic proteins, such as basic fibroblast growth factor and its antibody. Results suggest that under specific conditions, endothelial cells express an Angiogenin receptor that may mediate Angiogenin-stimulated DNA synthesis and proliferation and play an important role in Angiogenin-induced angiogenesis.
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characterization of mouse Angiogenin related protein implications for functional studies on Angiogenin
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Valentina Nobile, Bert L Vallee, Robert ShapiroAbstract:Abstract Angiogenin-related protein (Angrp), the putative product of a recently discovered mouse gene, shares 78% sequence identity with mouse Angiogenin (Ang). In the present study, the relationship of Angrp to Ang has been investigated by producing both proteins in bacteria and comparing their functional properties. We find that mouse Ang is potently angiogenic, but Angrp is not, even when assayed at relatively high doses. A deficiency in catalytic capacity, which is essential for the biological activity of Ang, does not appear to underlie Angrp's lack of angiogenicity. In fact, Angrp has somewhat greater ribonucleolytic activity toward tRNA and dinucleotide substrates than does Ang. Instead, an inability to bind cellular receptors is implicated since Angrp does not inhibit Ang-induced angiogenesis. Poor conservation of the Ang receptor recognition sequence 58-69 in Angrp most likely contributes to this defect. However, other substitutions must also influence receptor binding since an Angrp quadruple mutant that is identical to Ang in this segment still lacks both angiogenic activity and the capacity to inhibit Ang. The functional differences between Ang and Angrp, together with evidence presented herein that Angrp is regulated differently than Ang, suggest that the roles of the two proteins in vivo may be quite distinct.
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crystal structure of human Angiogenin reveals the structural basis for its functional divergence from ribonuclease
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: K.r. Acharya, James F. Riordan, R Shapiro, Simon C Allen, Bert L ValleeAbstract:Angiogenin, a potent inducer of neovascularization, is the only angiogenic molecule known to exhibit ribonucleolytic activity. Its overall structure, as determined at 2.4 A, is similar to that of pancreatic ribonuclease A, but it differs markedly in several distinct areas, particularly the ribonucleolytic active center and the putative receptor binding site, both of which are critically involved in biological function. Most strikingly, the site that is spatially analogous to that for pyrimidine binding in ribonuclease A differs significantly in conformation and is "obstructed" by glutamine-117. Movement of this and adjacent residues may be required for substrate binding to Angiogenin and, hence, constitute a key part of its mechanism of action.
Takanori Tsuji - One of the best experts on this subject based on the ideXlab platform.
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Neamine inhibits xenografic human tumor growth and angiogenesis in athymic mice.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2005Co-Authors: Saori Hirukawa, Takanori Tsuji, Karen A. Olson, Guo Fu HuAbstract:We have previously shown that the aminoglycoside antibiotic neomycin blocks the nuclear translocation of Angiogenin and inhibits its angiogenic activity. However, neomycin has not been considered as a favorable drug candidate for clinical development because of its known nephrotoxicity and ototoxicity. The aim of this study is to determine whether neamine, a nontoxic derivative of neomycin, possesses antitumor activity. The effect of neamine on the nuclear translocation of Angiogenin was examined by means of immunofluorescence and Western blotting. The antitumor activity of neamine was determined with three different animal models. Neamine effectively blocked the nuclear translocation of Angiogenin in endothelial cells and inhibited Angiogenin-induced cell proliferation. It inhibited the establishment of human tumor xenografts in athymic mice in both ectopic and orthotopic tumor models. It also inhibited the progression of established human tumor transplants, whereas the structurally related antibiotic paromomycin had no effect. Immunohistochemical staining showed that both angiogenesis and cancer cell proliferation are inhibited by neamine. These results suggest that the nontoxic aminoglycoside antibiotic neamine is an effective inhibitor of nuclear translocation of Angiogenin and may serve as an inhibitor for Angiogenin-induced angiogenesis and cancer progression.
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neamine inhibits xenografic human tumor growth and angiogenesis in athymic mice
Clinical Cancer Research, 2005Co-Authors: Saori Hirukawa, Takanori Tsuji, Karen A. Olson, Guo Fu HuAbstract:Purpose: We have previously shown that the aminoglycoside antibiotic neomycin blocks the nuclear translocation of Angiogenin and inhibits its angiogenic activity. However, neomycin has not been considered as a favorable drug candidate for clinical development because of its known nephrotoxicity and ototoxicity. The aim of this study is to determine whether neamine, a nontoxic derivative of neomycin, possesses antitumor activity. Experimental Design: The effect of neamine on the nuclear translocation of Angiogenin was examined by means of immunofluorescence and Western blotting. The antitumor activity of neamine was determined with three different animal models. Results: Neamine effectively blocked the nuclear translocation of Angiogenin in endothelial cells and inhibited Angiogenin-induced cell proliferation. It inhibited the establishment of human tumor xenografts in athymic mice in both ectopic and orthotopic tumor models. It also inhibited the progression of established human tumor transplants, whereas the structurally related antibiotic paromomycin had no effect. Immunohistochemical staining showed that both angiogenesis and cancer cell proliferation are inhibited by neamine. Conclusion: These results suggest that the nontoxic aminoglycoside antibiotic neamine is an effective inhibitor of nuclear translocation of Angiogenin and may serve as an inhibitor for Angiogenin-induced angiogenesis and cancer progression.
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Angiogenin is translocated to the nucleus of hela cells and is involved in ribosomal rna transcription and cell proliferation
Cancer Research, 2005Co-Authors: Takanori Tsuji, Karen A. Olson, Koji Kishimoto, Yeqing Sun, Shumei Liu, Saori HirukawaAbstract:Angiogenin is an angiogenic protein known to play a role in rRNA transcription in endothelial cells. Nuclear translocation of Angiogenin in endothelial cells decreases as cell density increases and ceases when cells are confluent. Here we report that Angiogenin is constantly translocated to the nucleus of HeLa cells in a cell density-independent manner. Down-regulation of Angiogenin expression by antisense and RNA interference results in a decrease in rRNA transcription, ribosome biogenesis, proliferation, and tumorigenesis both in vitro and in vivo. Exogenous Angiogenin rescues the cells from antisense and RNA interference inhibition. The results showed that Angiogenin is constitutively translocated into the nucleus of HeLa cells where it stimulates rRNA transcription. Thus, besides its angiogenic activity, Angiogenin also plays a role in cancer cell proliferation.
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Endogenous Angiogenin in endothelial cells is a general requirement for cell proliferation and angiogenesis
Oncogene, 2004Co-Authors: Koji Kishimoto, Takanori Tsuji, Karen A. Olson, Guo Fu HuAbstract:Angiogenin is an angiogenic protein that undergoes nuclear translocation in endothelial cells where it accumulates in the nucleolus and stimulates rRNA transcription, a rate-limiting step in ribosome biogenesis, protein translation, and cell growth. Here, we report that Angiogenin is required for cell proliferation induced by various other angiogenic proteins including acidic and basic fibroblast growth factors (aFGF and bFGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF). Downregulation of Angiogenin in endothelial cells by small interfering RNA (siRNA) and antisense results in a decrease in rRNA transcription, ribosome biogenesis, and cell proliferation induced by these angiogenic factors. Inhibitors of the nuclear translocation of Angiogenin abolish the angiogenic activities of these factors. Stable Angiogenin antisense transfection in HeLa cells reduces tumor angiogenesis in athymic mice despite the elevated expression level of bFGF and VEGF. Thus, nuclear Angiogenin assumes an essential role in endothelial cell proliferation and is necessary for angiogenesis induced by other angiogenic factors. Angiogenin-stimulated rRNA transcription in endothelial cells may thus serve as a crossroad in the process of angiogenesis induced by various angiogenic factors.
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The nuclear function of Angiogenin in endothelial cells is related to rRNA production.
Biochemical and biophysical research communications, 2002Co-Authors: Takanori Tsuji, James F. RiordanAbstract:Angiogenin is a potent angiogenic protein whose inhibition is known to prevent human tumor growth in athymic mice. It is secreted by both tumor and normal cells; and interacts with endothelial and smooth muscle cells to induce a wide range of cellular responses including cell migration and invasion, proliferation, and formation of tubular structures. Angiogenin is rapidly endocytosed and translocated to the cell nucleus where it accumulates in the nucleolus and binds to DNA. Although nuclear translocation is necessary for its angiogenic activity, the nuclear function of Angiogenin is unclear. Here we report that exogenous Angiogenin enhances the production of 45S rRNA in endothelial cells, and reduction of endogenous Angiogenin inhibits its transcription. In a nuclear run-on assay, Angiogenin stimulates RNA synthesis including that containing the initiation site sequences of 45S rRNA. This suggests that the nuclear function of Angiogenin relates to its capacity to induce rRNA synthesis. Because rRNA transcription is essential for the synthesis of new ribosomes that are necessary for protein translation and cell growth, inhibition of Angiogenin-stimulated transcription of rRNA may inhibit angiogenesis and therefore, would serve as a molecular target for therapeutic intervention.
Guo Fu Hu - One of the best experts on this subject based on the ideXlab platform.
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Neamine inhibits xenografic human tumor growth and angiogenesis in athymic mice.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2005Co-Authors: Saori Hirukawa, Takanori Tsuji, Karen A. Olson, Guo Fu HuAbstract:We have previously shown that the aminoglycoside antibiotic neomycin blocks the nuclear translocation of Angiogenin and inhibits its angiogenic activity. However, neomycin has not been considered as a favorable drug candidate for clinical development because of its known nephrotoxicity and ototoxicity. The aim of this study is to determine whether neamine, a nontoxic derivative of neomycin, possesses antitumor activity. The effect of neamine on the nuclear translocation of Angiogenin was examined by means of immunofluorescence and Western blotting. The antitumor activity of neamine was determined with three different animal models. Neamine effectively blocked the nuclear translocation of Angiogenin in endothelial cells and inhibited Angiogenin-induced cell proliferation. It inhibited the establishment of human tumor xenografts in athymic mice in both ectopic and orthotopic tumor models. It also inhibited the progression of established human tumor transplants, whereas the structurally related antibiotic paromomycin had no effect. Immunohistochemical staining showed that both angiogenesis and cancer cell proliferation are inhibited by neamine. These results suggest that the nontoxic aminoglycoside antibiotic neamine is an effective inhibitor of nuclear translocation of Angiogenin and may serve as an inhibitor for Angiogenin-induced angiogenesis and cancer progression.
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neamine inhibits xenografic human tumor growth and angiogenesis in athymic mice
Clinical Cancer Research, 2005Co-Authors: Saori Hirukawa, Takanori Tsuji, Karen A. Olson, Guo Fu HuAbstract:Purpose: We have previously shown that the aminoglycoside antibiotic neomycin blocks the nuclear translocation of Angiogenin and inhibits its angiogenic activity. However, neomycin has not been considered as a favorable drug candidate for clinical development because of its known nephrotoxicity and ototoxicity. The aim of this study is to determine whether neamine, a nontoxic derivative of neomycin, possesses antitumor activity. Experimental Design: The effect of neamine on the nuclear translocation of Angiogenin was examined by means of immunofluorescence and Western blotting. The antitumor activity of neamine was determined with three different animal models. Results: Neamine effectively blocked the nuclear translocation of Angiogenin in endothelial cells and inhibited Angiogenin-induced cell proliferation. It inhibited the establishment of human tumor xenografts in athymic mice in both ectopic and orthotopic tumor models. It also inhibited the progression of established human tumor transplants, whereas the structurally related antibiotic paromomycin had no effect. Immunohistochemical staining showed that both angiogenesis and cancer cell proliferation are inhibited by neamine. Conclusion: These results suggest that the nontoxic aminoglycoside antibiotic neamine is an effective inhibitor of nuclear translocation of Angiogenin and may serve as an inhibitor for Angiogenin-induced angiogenesis and cancer progression.
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Endogenous Angiogenin in endothelial cells is a general requirement for cell proliferation and angiogenesis
Oncogene, 2004Co-Authors: Koji Kishimoto, Takanori Tsuji, Karen A. Olson, Guo Fu HuAbstract:Angiogenin is an angiogenic protein that undergoes nuclear translocation in endothelial cells where it accumulates in the nucleolus and stimulates rRNA transcription, a rate-limiting step in ribosome biogenesis, protein translation, and cell growth. Here, we report that Angiogenin is required for cell proliferation induced by various other angiogenic proteins including acidic and basic fibroblast growth factors (aFGF and bFGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF). Downregulation of Angiogenin in endothelial cells by small interfering RNA (siRNA) and antisense results in a decrease in rRNA transcription, ribosome biogenesis, and cell proliferation induced by these angiogenic factors. Inhibitors of the nuclear translocation of Angiogenin abolish the angiogenic activities of these factors. Stable Angiogenin antisense transfection in HeLa cells reduces tumor angiogenesis in athymic mice despite the elevated expression level of bFGF and VEGF. Thus, nuclear Angiogenin assumes an essential role in endothelial cell proliferation and is necessary for angiogenesis induced by other angiogenic factors. Angiogenin-stimulated rRNA transcription in endothelial cells may thus serve as a crossroad in the process of angiogenesis induced by various angiogenic factors.