title: Deferoxamine-induced increase in the intracellular iron levels in highly aggressive breast cancer cells leads to increased cell migration by enhancing TNF-α-dependent NF-κB signaling and TGF-β signaling.
abstract: Recent studies have suggested that excess iron accumulation may be a risk factor for breast cancer. However the role of iron in breast cancer metastasis has remained unclear. The major goal of our study is to investigate the roles of iron in breast cancer metastasis. We modulated the intracellular iron levels of human breast cancer cells, including the aggressive MDA-MB-231 cells and non-aggressive MCF-7 cells, by using Deferoxamine (DFO) - a most widely used iron chelator. We found that DFO treatment could deplete intracellular iron in MCF-7 cells. In contrast, DFO treatment led to a significant increase in the intracellular iron level in MDA-MB-231 cells. The MDA-MB-231 cells with the increased intracellular iron level exhibited increases in both mesenchymal markers and cell migration. Furthermore, the DFO-treated MDA-MB-231 cells showed increases in both tumor necrosis factor α (TNF-α)-induced nuclear factor kappa B (NF-κB) signaling and transforming growth factor-β (TGF-β) signaling, which could contribute to the enhanced cell migration. Collectively, our study has provided the first evidence suggesting that increased intracellular iron levels could lead to enhanced migration of aggressive breast cancer cells by increasing TNF-α-dependent NF-κB signaling and TGF-β signaling. Our study has also suggested that caution should be taken when DFO is applied for treating breast cancer cells, since DFO could produce differential effects on the intracellular iron levels for aggressive breast cancer cells and non-aggressive breast cancer cells.
authors.affiliation: Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, People's Republic of China; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China. Electronic address: pingliu@sjtu.edu.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, People's Republic of China; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
authors.forename: Kun
authors.initials: K
authors.lastname: He
authors.affiliation: Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, People's Republic of China; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
authors.forename: Hongjiao
authors.initials: H
authors.lastname: Song
authors.affiliation: Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, People's Republic of China; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
authors.forename: Zhufeng
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, People's Republic of China; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
authors.forename: Weihai
authors.initials: W
authors.lastname: Yin
authors.affiliation: Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, People's Republic of China; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
authors.forename: Lisa X
authors.initials: LX
authors.lastname: Xu
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007501:Iron / Q000819:agonists / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D042361:Mammary Glands, Human / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D007502:Iron Chelating Agents; D016328:NF-kappa B; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C000604407:SNAI1 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D000071250:Snail Family Transcription Factors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007501:Iron; D003676:Deferoxamine
keywords: Breast cancer cells; DFO; Iron; Migration