Regulatory effects of gallium on transferrin-independent iron uptake by human leukemic HL60 cells.
Gallium, a pharmacologically important metal, resembles iron with respect to transferrin (Tf) binding and Tf receptor-mediated cellular uptake. In the present study, we examined the effect of gallium on Tf-independent iron uptake by HL60 cells. In contrast to the inhibitory effect of Tf-gallium on Tf-iron uptake, gallium nitrate, in a time-, temperature-, and concentration-dependent manner, stimulated Tf-independent uptake of iron-nitrilotriacetic acid (Fe-NTA). Preexposure of cells to gallium followed by removal of gallium also resulted in sustained stimulation of iron uptake. The anti-Tf receptor monoclonal antibody 42/6 blocked Tf-iron uptake, but had no effect on gallium-induced stimulation of Tf-independent iron uptake. Gallium increased the number of cell membrane iron-binding sites, without a change in their affinity for iron. Ferric chloride stimulated Tf-independent gallium uptake. Although gallium nitrate inhibited cell growth in Tf-free medium, cellular proliferation was restored by Fe-NTA. Gallium and iron appear to share the same Tf-independent cellular uptake system in HL60 cells. Exposure of cells to gallium results in the activation of cell membrane non-Tf iron carriers that may play a role in overcoming the Tf-independent growth-inhibitory effects of gallium.
Chitambar
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Department of Medicine, Medical College of Wisconsin, Milwaukee 53226.
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D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002712:Chlorides; D005290:Ferric Compounds / Q000494:pharmacology; D005708:Gallium / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute; D011990:Receptors, Transferrin / Q000276:immunology / Q000502:physiology; D014168:Transferrin / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002712:Chlorides; D005290:Ferric Compounds; D011990:Receptors, Transferrin; D014168:Transferrin; D005708:Gallium; D007501:Iron; C024555:ferric chloride; C027235:gallium nitrate