Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA.
Department of Electronic Engineering, National Kaohsiung University of Science and Technology, Kaohsiung 80778, Taiwan.
Int J Mol Sci. 2024 Aug 16;25(16):8941. doi: 10.3390/ijms25168941.
Iron is an essential element for human health. In humans, dysregulated iron homeostasis can result in a variety of disorders and the development of cancers. Enhanced uptake, redistribution, and retention of iron in cancer cells have been suggested as an "iron addiction" pattern in cancer cells. This increased iron in cancer cells positively correlates with rapid tumor growth and the epithelial-to-mesenchymal transition, which forms the basis for tumor metastasis. However, the source of iron and the mechanisms cancer cells adopt to actively acquire iron is not well understood. In the present study, we report, for the first time, that the peptide hormone, prolactin, exhibits a novel function in regulating iron distribution, on top of its well-known pro-lactating role. When stimulated by prolactin, breast cancer cells increase CD44, a surface receptor mediating the endocytosis of hyaluronate-bound iron, resulting in the accumulation of iron in cancer cells. In contrast, macrophages, when treated by prolactin, express more ferroportin, the only iron exporter in cells, giving rise to net iron output. Interestingly, when co-culturing macrophages with pre-stained labile iron pools and cancer cells without any iron staining, in an iron free condition, we demonstrate direct iron flow from macrophages to cancer cells. As macrophages are one of the major iron-storage cells and it is known that macrophages infiltrate tumors and facilitate their progression, our work therefore presents a novel regulatory role of prolactin to drive iron flow, which provides new information on fine-tuning immune responses in tumor microenvironment and could potentially benefit the development of novel therapeutics.
铁是人体健康所必需的元素。在人体中，铁稳态失调可导致多种疾病和癌症的发生。研究表明，癌细胞中铁的摄取、再分配和保留增强，是癌细胞中的一种“铁成瘾”模式。癌细胞中增加的铁与肿瘤的快速生长和上皮-间充质转化呈正相关，而后者是肿瘤转移的基础。然而，铁的来源以及癌细胞主动获取铁的机制尚未完全清楚。在本研究中，我们首次报道，除了其众所周知的泌乳作用外，肽激素催乳素还具有调节铁分布的新功能。当受到催乳素刺激时，乳腺癌细胞增加了 CD44，这是一种介导透明质酸结合铁内吞作用的表面受体，导致癌细胞中铁的积累。相比之下，当巨噬细胞受到催乳素处理时，表达更多的铁蛋白，这是细胞中唯一的铁输出蛋白，导致净铁输出。有趣的是，当我们在无铁条件下将预染不稳定铁池的巨噬细胞与无任何铁染色的癌细胞共培养时，我们证明了铁从巨噬细胞直接流向癌细胞。由于巨噬细胞是主要的铁储存细胞之一，而且众所周知巨噬细胞浸润肿瘤并促进其进展，因此我们的工作提出了催乳素驱动铁流的新调节作用，这为肿瘤微环境中免疫反应的精细调控提供了新信息，并可能有益于新型治疗方法的开发。
