Abstract
Novel treatment approaches are needed for children with advanced neuroblastoma. Studies with neuroblastoma cells have indicated the presence of a hypoxia-driven vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-1 autocrine loop modulating hypoxia-inducible factor-1alpha (HIF-1alpha). Whether other receptor tyrosine kinases (RTKs) are capable of modulating HIF-1alpha levels and whether RTKs can regulate HIF-2alpha as well is largely unknown. We evaluated neuroblastoma cell lines for expression of various RTKs. Although cell lines were heterogeneous in the expression of VEGFR-1, -3, c-Kit and RET, most cells expressed PDGFR-alpha and -beta. Ligand-induced activation of multiple RTKs upregulated HIF-1alpha levels, whereas activation of VEGFR-1 alone upregulated HIF-2alpha. Multitargeted tyrosine kinase inhibitor sunitinib reduced hypoxia-induced rises in HIF-1alpha and HIF-2alpha through mechanisms involving effects on both mRNA levels and protein stability. In addition, sunitinib and sorafenib had direct effects on tumor cell viability in vitro. In a neuroblastoma xenograft model, tumor growth inhibition by sunitinib was associated with inhibition of angiogenesis and reduced HIF-1alpha levels. These findings show that multiple RTKs may regulate the HIF axis in normoxia and hypoxia and suggest that multikinase inhibitors may exert antiangiogenic effects not only by direct effects on endothelial cells, but also by blocking compensatory hypoxia- and ligand-induced changes in HIF-1alpha and HIF-2alpha.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Blotting, Western
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Cell Movement
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Humans
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Hypoxia / metabolism*
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Immunoenzyme Techniques
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Indoles / pharmacology
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Neovascularization, Pathologic / prevention & control
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Neuroblastoma / drug therapy
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Neuroblastoma / metabolism*
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Proto-Oncogene Proteins c-kit / genetics
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Proto-Oncogene Proteins c-kit / metabolism
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Proto-Oncogene Proteins c-ret / antagonists & inhibitors
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Proto-Oncogene Proteins c-ret / metabolism
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Pyrroles / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Receptor Protein-Tyrosine Kinases / metabolism*
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Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
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Receptor, Platelet-Derived Growth Factor beta / genetics
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Receptor, Platelet-Derived Growth Factor beta / metabolism
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Receptors, Interleukin-2 / physiology
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Reverse Transcriptase Polymerase Chain Reaction
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Sunitinib
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Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-1 / metabolism
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Vascular Endothelial Growth Factor Receptor-3 / genetics
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Vascular Endothelial Growth Factor Receptor-3 / metabolism
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Xenograft Model Antitumor Assays
Substances
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Angiogenesis Inhibitors
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Basic Helix-Loop-Helix Transcription Factors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Indoles
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Pyrroles
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RNA, Messenger
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RNA, Small Interfering
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Receptors, Interleukin-2
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endothelial PAS domain-containing protein 1
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Proto-Oncogene Proteins c-kit
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Proto-Oncogene Proteins c-ret
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RET protein, human
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Receptor Protein-Tyrosine Kinases
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Receptor, Platelet-Derived Growth Factor beta
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factor Receptor-3
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Sunitinib