School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200000, China.
School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200000, China.
Int J Mol Sci. 2019 Oct 8;20(19):4952. doi: 10.3390/ijms20194952.
In our previous study, Deferoxamine (DFO) increased the iron concentration by upregulating the expression levels of TfR1 and DMT1 and exacerbated the migration of triple-negative breast cancer cells. However, the mechanisms of iron distribution and utilization in triple-negative breast cancer cells with a DFO-induced iron deficiency are still unclear. In this study, triple-negative MDA-MB-231 and estrogen receptor (ER)-positive MCF-7 breast cancer cells were used to investigate the mechanisms of iron distribution and utilization with a DFO-induced iron deficiency. We found that the mitochondrial iron concentration was elevated in MDA-MB-231 cells, while it was decreased in MCF-7 cells after DFO treatment. The cellular and mitochondrial reactive oxygen species (ROS) levels increased in both breast cancer cell types under DFO-induced iron-deficient conditions. However, the increased ROS levels had different effects on the different breast cancer cell types: Cell viability was inhibited and apoptosis was enhanced in MCF-7 cells, but cell viability was maintained and cell migration was promoted in MDA-MB-231 cells through the ROS/NF-κB and ROS/TGF-β signaling pathways. Collectively, this study suggests that under DFO-induced iron-deficient conditions, the increased mitochondrial iron levels in triple-negative MDA-MB-231 breast cancer cells would generate large amounts of ROS to activate the NF-κB and TGF-β signaling pathways to promote cell migration.
在我们之前的研究中，去铁胺 (DFO) 通过上调 TfR1 和 DMT1 的表达水平来增加铁浓度，并加剧三阴性乳腺癌细胞的迁移。然而，DFO 诱导铁缺乏时三阴性乳腺癌细胞中铁的分布和利用机制仍不清楚。在这项研究中，我们使用三阴性 MDA-MB-231 和雌激素受体 (ER) 阳性 MCF-7 乳腺癌细胞来研究 DFO 诱导铁缺乏时铁的分布和利用机制。我们发现，DFO 处理后 MDA-MB-231 细胞中线粒体铁浓度升高，而 MCF-7 细胞中铁浓度降低。在 DFO 诱导的铁缺乏条件下，两种乳腺癌细胞类型中的细胞和线粒体活性氧 (ROS) 水平均升高。然而，增加的 ROS 水平对不同的乳腺癌细胞类型有不同的影响：在 MCF-7 细胞中，细胞活力受到抑制，细胞凋亡增强，但通过 ROS/NF-κB 和 ROS/TGF-β 信号通路，MDA-MB-231 细胞中的细胞活力得以维持，细胞迁移得到促进。综上所述，本研究表明，在 DFO 诱导的铁缺乏条件下，三阴性 MDA-MB-231 乳腺癌细胞中线粒体铁水平的升高会产生大量的 ROS，激活 NF-κB 和 TGF-β 信号通路，促进细胞迁移。
