Journal of Clinical & Experimental Pathology
Open Access

Abstract

Ascorbate stimulates dietary iron (Fe) absorption and non-transferrin Fe uptake. However, under physiological conditions, most cellular Fe is delivered by the serum Fe transport protein, transferrin. This process is enhanced in neoplasia. For the first time, we have examined ascorbate��?s role in this crucial process. At physiological levels, ascorbate doubled 59Fe uptake from transferrin in a range of neoplastic and other cells. Although ascorbate both increased ferritin levels and increased 59Fe-ferritin accumulation, such effects were not responsible for the enhanced 59Fe uptake. Ascorbate was found to be required intracellularly, and experiments with L-ascorbate analogs indicate ascorbate��?s reducing ene-diol moiety is necessary, for its stimulatory activity. Ascorbate's stimulatory effect was not due to an ascorbate-dependent increase in cellular glutathione or NADPH. Ascorbate also did not affect expression of transferrin receptors 1 or 2 (TfRs 1 or 2), 125I-transferrin cellular flux or expression of the endosomal ferrireductase, six transmembrane epithelial antigen of the prostate (Steap3). However, TfRs, endocytosis, vATPase activity and endosomal acidification were required. Therefore, ascorbate modulates the classical transferrin Fe uptake pathway, probably by modulating endosomal ferrireductase activity. These findings have ramifications for understanding how transferrin-derived Fe is reduced prior to its transport through endosomal ferrous-selective transporters such as the divalent metal transporter 1 (DMT1) in neoplastic cells.

Biography

Email: darius.lane@sydney.edu.au