Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells.
Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells.
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DOI：
10.1038/s42255-021-00406-7
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发表时间：
2021-07
影响因子：
20.8
通讯作者：
Shah YM
中科院分区：
文献类型：
--
作者：
Schwartz AJ;Goyert JW;Solanki S;Kerk SA;Chen B;Castillo C;Hsu PP;Do BT;Singhal R;Dame MK;Lee HJ;Spence JR;Lakhal-Littleton S;Vander Heiden MG;Lyssiotis CA;Xue X;Shah YM
结直肠癌（CRC）需要大量的铁储存，但CRC调节局部铁处理和代谢利用铁的完整机制知之甚少。我们证明，肝源性，内分泌调节全身铁平衡，铁调素，激活异位结直肠癌。铁调素结合唯一已知的哺乳动物铁输出细胞膜铁转运蛋白，导致膜铁转运蛋白降解和细胞内铁捕获。在散发性CRC模型中，与野生型同窝小鼠相比，结肠肿瘤上皮中铁调素基因特异性缺陷的小鼠表现出肿瘤数量、负荷和大小的显著降低，而膜铁转运蛋白缺失加重了这些肿瘤参数。为了进一步了解铁在CRC中的生物化学和代谢利用，我们对三维患者来源的CRC肿瘤肠模型进行了代谢组学研究，发现铁在CRC中优先用于核苷酸的生产。这些代谢组学发现在我们的铁调素/ferroportin小鼠CRC模型中得到了重现。从机制上讲，我们的数据表明线粒体功能的下降会改变铁螯合后的核苷酸合成。用外源性补充核苷恢复核苷酸代谢导致在铁螯合剂存在下部分拯救患者来源的肿瘤肠样和CRC细胞系的生长。此外，连接线粒体呼吸和核苷酸合成的关键代谢物天冬氨酸也部分挽救了缺铁CRC细胞的生长。总的来说，这些数据表明，异位hepcidin在肿瘤上皮细胞建立一个轴，以降解膜铁转运蛋白和螯合铁在结直肠肿瘤，以保持核苷酸池和维持增殖。
Colorectal cancer (CRC) requires massive iron stores, but the complete mechanisms by which CRC modulates local iron handling and metabolically leverages iron are poorly understood. We demonstrate that the liver-derived, endocrine regulator of systemic iron balance, hepcidin, is activated ectopically in CRC. Hepcidin binds to the only known mammalian iron exporter ferroportin, resulting in degradation of ferroportin and intracellular iron trapping. Mice deficient for the hepcidin gene specifically in colon tumor epithelium exhibited significant decreases in tumor number, burden, and size compared to wild-type littermates in a sporadic model of CRC, whereas ferroportin deletion exacerbated these tumor parameters. To further understand the biochemical and metabolic utilization of iron in CRC, we subjected a three-dimensional patient-derived CRC tumor enteroid model to metabolomics and found that iron is prioritized in CRC for the production of nucleotides. These metabolomics findings were recapitulated in our hepcidin/ferroportin mouse CRC models. Mechanistically, our data suggest that a decrease in mitochondrial function alters nucleotide synthesis following iron chelation. Restoration of nucleotide metabolism with exogenous supplementation of nucleosides led to a partial rescue of growth in patient-derived tumor enteroids and CRC cell lines in the presence of an iron chelator. Moreover, aspartate, a critical metabolite which links mitochondrial respiration and nucleotide synthesis, also partially rescued growth of iron deficient CRC cells. Collectively, these data suggest that ectopic hepcidin in the tumor epithelium establishes an axis to degrade ferroportin and sequester iron in colorectal tumors in order to maintain the nucleotide pool and sustain proliferation.
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