title: Cell-permeable iron inhibits vascular endothelial growth factor receptor-2 signaling and tumor angiogenesis.
abstract: Angiogenesis is important for tumor growth and metastasis. Hypoxia in tumors drives this angiogenic response by stabilizing Hypoxia Inducible Factors (HIF) and target genes like Vascular Endothelial Growth Factor (VEGF). HIF stability is regulated by Prolylhydroxylases (PHD)-mediated modification. Iron is an important cofactor in regulating the enzymatic activity of PHDs. Reducing intracellular iron, for instance, mimics hypoxia and induces a pro-angiogenic response. It is hypothesized that increasing the intracellular iron levels will have an opposite, anti-angiogenic effect. We tested this hypothesis by perturbing iron homeostasis in endothelial cells using a unique form of iron, Ferric Ammonium Citrate (FAC). FAC is a cell-permeable form of iron, which can passively enter into cells bypassing the transferrin receptor mediated uptake of transferrin-bound iron. Our studies show that FAC does not decrease the levels of HIF-1α and HIF-2α in endothelial cells but inhibits the autocrine stimulation of VEGF-Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) system by blocking receptor tyrosine kinase phosphorylation. FAC inhibits VEGF-induced endothelial cell proliferation, migration, tube formation and sprouting. Finally, systemic administration of FAC inhibits VEGF and tumor cell-induced angiogenesis in vivo. In conclusion, our studies show that cell-permeable iron attenuates VEGFR-2 mediated signaling and inhibits tumor angiogenesis.
authors: Department of Pharmacology, Masonic Comprehensive Cancer Center, Minneapolis, MN 55455, USA.|Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Devika
authors: D
authors: Kir
authors: Department of Pharmacology, Masonic Comprehensive Cancer Center, Minneapolis, MN 55455, USA.
authors: Manju
authors: M
authors: Saluja
authors: Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Shrey
authors: S
authors: Modi
authors: Department of Pharmacology, Masonic Comprehensive Cancer Center, Minneapolis, MN 55455, USA.
authors: Annapoorna
authors: A
authors: Venkatachalam
authors: Department of Pharmacology, Masonic Comprehensive Cancer Center, Minneapolis, MN 55455, USA.
authors: Erica
authors: E
authors: Schnettler
authors: Department of Pharmacology, Masonic Comprehensive Cancer Center, Minneapolis, MN 55455, USA.|Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.|Present address: Department of Surgery, University of Miami, FL 33136, USA.
authors: Sabita
authors: S
authors: Roy
authors: Department of Pharmacology, Masonic Comprehensive Cancer Center, Minneapolis, MN 55455, USA.|Present address: Department of Surgery, University of Miami, FL 33136, USA.
authors: Sundaram
authors: S
authors: Ramakrishnan
mesh_terms: D019898:Autocrine Communication; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism*; D002463:Cell Membrane Permeability; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000502:physiology*; D005290:Ferric Compounds / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D018448:Models, Immunological; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D064828:Prolyl Hydroxylases / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005290:Ferric Compounds; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron; D064828:Prolyl Hydroxylases; D000644:Quaternary Ammonium Compounds; D020794:Receptor Protein-Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C000588866:KDR protein, human; C013531:ferric ammonium citrate
keywords: angiogenesis; cell-permeable iron; ferric ammonium citrate; receptor phosphorylation; vascular endothelial growth factor