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Cell-permeable iron inhibits vascular endothelial growth factor receptor-2
signaling and tumor angiogenesis
#MMPMID27589831
Kir D
; Saluja M
; Modi S
; Venkatachalam A
; Schnettler E
; Roy S
; Ramakrishnan S
Oncotarget
2016[Oct]; 7
(40
): 65348-65363
PMID27589831
show ga
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-1? and HIF-2? 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.
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