Davies Neil P, Suryo Rahmanto Yohan, Chitambar Christopher R, Richardson Des R
Children's Cancer Institute Australia for Medical Research, the Iron Metabolism and Chelation Program, Randwick, Sydney, New South Wales.
J Pharmacol Exp Ther. 2006 Apr;317(1):153-62. doi: 10.1124/jpet.105.099044. Epub 2005 Dec 22.
Gallium (Ga) shows significant antitumor activity by markedly interfering with iron (Fe) metabolism, and (67)Ga is used as a radio-imaging agent for cancer detection. Therefore, the mechanisms involved in (67)Ga uptake, metabolism, and resistance are critical to understand. The development of tumor lines that are gallium-resistant suggests (67)Ga uptake may be different in these cells, providing an opportunity for understanding intracellular (67)Ga and (59)Fe transport and gallium resistance. In this study, gallium-resistant cells were used to assess (67)Ga and (59)Fe uptake using native polyacrylamide gel electrophoresis autoradiography. In contrast to the common view that (67)Ga and (59)Fe 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 (59)Fe, little (67)Ga is incorporated into ferritin, with most present as a labile (67)Ga pool. We also report unique changes in (67)Ga and (59)Fe 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 (67)Ga and (59)Fe 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 (67)Ga and (59)Fe use the same or similar uptake pathways, we show that their distribution and trafficking is markedly different in R and S cells.
镓（Ga）通过显著干扰铁（Fe）代谢显示出显著的抗肿瘤活性，并且（67）Ga被用作癌症检测的放射性成像剂。因此，了解参与（67）Ga摄取、代谢和抗性的机制至关重要。耐镓肿瘤细胞系的发展表明这些细胞中（67）Ga的摄取可能不同，这为理解细胞内（67）Ga和（59）Fe的转运以及镓抗性提供了机会。在本研究中，使用耐镓细胞通过天然聚丙烯酰胺凝胶电泳放射自显影来评估（67）Ga和（59）Fe的摄取。与（67）Ga和（59）Fe使用相同摄取途径的普遍观点相反，我们表明这两种金属离子在对镓耐药（R）或敏感（S）的细胞中的运输是不同的。事实上，与（59）Fe相比，很少有（67）Ga掺入铁蛋白中，大多数以不稳定的（67）Ga池形式存在。我们还报告了R细胞和S细胞之间（67）Ga和（59）Fe运输的独特变化。特别是，在R细胞中，存在一种在S细胞中未观察到的独特的转铁蛋白-转铁蛋白受体1-血色素沉着症蛋白（HFE）复合物（条带B）。此外，由于HFE调节铁和镓的摄取，与S细胞相比，R细胞中的两种Tf-TfR1-HFE复合物可能参与了（67）Ga和（59）Fe摄取的减少。在S细胞中，鉴定出一种在R细胞中不存在的新型铁结合中间体（条带D），它可能是对镓的“敏感因子”。与（67）Ga和（59）Fe使用相同或相似摄取途径的普遍观点相反，我们表明它们在R细胞和S细胞中的分布和运输明显不同。
