Abstract
BackgroundThe molecular mechanisms by which iron is physiologically transported trough the cellular membranes are still only partially understood. Several studies indicate that a reduction step of ferric iron to ferrous is necessary, both in the case of transferrin-mediated and transferrin-independent iron uptake. Recent studies from our laboratory described gamma-glutamyltransferase activity (GGT) as a factor capable to effect iron reduction in the cell microenvironment. GGT is located on the outer aspect of plasma membrane of most cell types, and is often expressed at high levels in malignant tumors and their metastases. The present study was aimed at verifying the possibility that GGT-mediated iron reduction may participate in the process of cellular iron uptake.ResultsFour distinct human tumor cell lines, exhibiting different levels of GGT activity, were studied. The uptake of transferrin-bound iron was investigated by using 55Fe-loaded transferrin, as well as by monitoring fluorimetrically the intracellular iron levels in calcein-preloaded cells. Transferrin-independent iron uptake was investigated using 55Fe complexed by nitrilotriacetic acid (55Fe-NTA complex).The stimulation of GGT activity, by administration to cells of the substrates glutathione and glycyl-glycine, was generally reflected in a facilitation of transferrin-bound iron uptake. The extent of such facilitation was correlated with the intrinsic levels of the enzyme present in each cell line. Accordingly, inhibition of GGT activity by means of two independent inhibitors, acivicin and serine/boric acid complex, resulted in a decreased uptake of transferrin-bound iron. With Fe-NTA complex, the inhibitory effect – but not the stimulatory one – was also observed.ConclusionIt is concluded that membrane GGT can represent a facilitating factor in iron uptake by GGT-expressing cancer cells, thus providing them with a selective growth advantage over clones that do not possess the enzyme.
Highlights
The molecular mechanisms by which iron is physiologically transported trough the cellular membranes are still only partially understood
As a confirmation of the inhibitory effect of acivicin, the same effect was observed in cells after gamma-glutamyl transpeptidase (GGT) inhibition by the structurally independent, competitive inhibitor serine/boric acid complex (SBC)
The results of the present study suggest that GGT activity expressed by tumor cells may play a positive role in the uptake of transferrin-bound iron
Summary
The molecular mechanisms by which iron is physiologically transported trough the cellular membranes are still only partially understood. Recent studies from our laboratory described gammaglutamyltransferase activity (GGT) as a factor capable to effect iron reduction in the cell microenvironment. Cells had to devise specific strategies to solubilize and absorb the metal These include i) systems capable to effect the reduction of ferric ions to the more soluble ferrous form, and ii) the use of proteins capable to transport ferric iron as such, such as e.g. transferrins [3]. Other studies have suggested that another critical step in cellular uptake of Tfbound iron may be the reduction of ferric iron to ferrous [6], and several molecular species acting as reductants have been described, including the superoxide anion, ascorbic acid and thiol compounds [7]. As recently pointed out by Kwok et al.[8], lines of evidence suggest that Fe3+ reduction takes place after uptake, as Fe is released from endosomes into the cytosol
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