Cobalt induces hypoxia-inducible factor-1alpha (HIF-1alpha) in HeLa cells by an iron-independent, but ROS-, PI-3K- and MAPK-dependent mechanism.
The iron-chelator desferrioxamine (DFO) and the transition metal cobalt induce hypoxia-inducible factor-1alpha (HIF-1alpha) in normoxia. DFO stabilizes HIF-1alpha from proteolysis by inhibiting the activity of iron-dependent prolyl hydroxylases, but the mechanism of action of cobalt is not fully elucidated. The purpose of this study was to examine the regulation of HIF-1alpha induction and HeLa cell proliferation by cobalt and the role of iron in these processes. Our results show that, unlike DFO, induction of transcriptionally active HIF-1alpha by CoCl2 cannot be abrogated by the addition of excess Fe3+, but involves the production of reactive oxygen species (ROS) and the operation of the phosphatidylinositol-3 kinase (PI-3K) and MAPK pathways. CoCl2, as well as DFO, decreased HeLa cell proliferation, but these effects were reversed by the addition of Fe3+. We conclude that the effect of cobalt on cell proliferation is iron-dependent, while its effects on HIF-1alpha induction are ROS- and signaling pathways-dependent, but iron-independent.
Triantafyllou
Anastasia
A
Laboratory of Biochemistry, School of Medicine, University of Thessaly, 22 Papakyriazi Street, 41222, Larissa, Greece.
Liakos
Panagiotis
P
Tsakalof
Andreas
A
Georgatsou
Elena
E
Simos
George
G
Bonanou
Sophia
S
D049109:Cell Proliferation; D003035:Cobalt / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007501:Iron / Q000378:metabolism*; D007700:Kinetics; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species; D015398:Signal Transduction
D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D003035:Cobalt; D004247:DNA; D007501:Iron; D019869:Phosphatidylinositol 3-Kinases; D003676:Deferoxamine