Cell-permeable iron inhibits vascular endothelial growth factor receptor-2 signaling and tumor angiogenesis

Devika Kir, Manju Saluja, Shrey Modi, Annapoorna Venkatachalam, Erica Schnettler, Sabita Roy, Sundaram Ramakrishnan

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)65348-65363
Number of pages16
Issue number40
StatePublished - 2016

Bibliographical note

Funding Information:
We thank Dr. Ashok Saluja and his colleagues for their help in flow cytometric analyses. This work was supported in part by a grant from National Institute on Drug Abuse DA031202, National Institute of Health DA037843 and Shirley Ann Sparboe Foundation for Women's Cancer Research.


  • Angiogenesis
  • Cell-permeable iron
  • Ferric ammonium citrate
  • Receptor phosphorylation
  • Vascular endothelial growth factor


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