Resistance to the Antineoplastic Agent Gallium Nitrate Results in Marked Alterations in Intracellular Iron and Gallium Trafficking: Identification of Novel Intermediates

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Abstract
Gallium (Ga) shows significant antitumor activity by markedly interfering with iron (Fe) metabolism, and 67Ga is used as a radio-imaging agent for cancer detection. Therefore, the mechanisms involved in 67Ga uptake, metabolism, and resistance are critical to understand. The development of tumor lines that are gallium-resistant suggests 67Ga uptake may be different in these cells, providing an opportunity for understanding intracellular 67Ga and 59Fe transport and gallium resistance. In this study, gallium-resistant cells were used to assess 67Ga and 59Fe uptake using native polyacrylamide gel electrophoresis autoradiography. In contrast to the common view that 67Ga and 59Fe use the same uptake pathways, we show that the trafficking of these two metal ions is different in cells either resistant (R) or sensitive (S) to gallium. Indeed, in contrast to 59Fe, little 67Ga is incorporated into ferritin, with most present as a labile 67Ga pool. We also report unique changes in 67Ga and 59Fe trafficking between R and S cells. In particular, in R cells, there was a distinct transferrin-transferrin receptor 1-hemochromatosis protein (HFE) complex (band B) not observed in S cells. Furthermore, because HFE regulates iron and gallium uptake, the two Tf-TfR1-HFE complexes in R cells may be involved in reduced 67Ga and 59Fe uptake compared with S cells. In S cells, a novel iron-binding intermediate (band D) was identified that was not present in R cells and may be a “sensitivity factor” to gallium. In contrast to the general view that 67Ga and 59Fe use the same or similar uptake pathways, we show that their distribution and trafficking is markedly different in R and S cells.
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