title: Deferoxamine promotes MDA-MB-231 cell migration and invasion through increased ROS-dependent HIF-1α accumulation.
abstract: OBJECTIVE
  Deferoxamine (DFO), an iron chelator, has been reported to induce hypoxia-inducible factor-1α (HIF-1α) expression. HIF-1α plays a critical role in promoting tumor metastasis. However, the molecular mechanisms underlying induction of HIF-1α in breast cancer cells remain unknown. Our aim was to ascertain whether DFO enhanced cancer metastasis in MDA-MB-231 cells.
  
  
  METHODS
  Cellular reactive oxygen species (ROS) was measured by flow cytometry. Cell migration was determined by wound healing and transwell assays. Protein and mRNA expression were detected by western blotting and RT-PCR, respectively.
  
  
  RESULTS
  DFO treatment enhanced cell migration and invasion, while HIF-1α expression was significantly up-regulated at the post-transcriptional level. However, treatment with a NADPH oxidase inhibitor, diphenyleneiodonium (DPI), strongly inhibited ROS generation and HIF-1α expression, as well as cell migration and invasion. Notably, DFO treatment increased extracellular signal-regulated kinase (ERK)1/2 phosphorylation. Inhibition of ROS production with DPI attenuated DFO-induced ERK1/2 activation. Moreover, a MEK1 inhibitor, PD98059, suppressed DFO-induced cell migration and invasion.
  
  
  CONCLUSIONS
  DFO-induced HIF-1α expression involves a cascade of signaling events including ROS generation, activation of ERK signaling, and subsequent promotion of cell migration and invasion. These findings indicate a risk associated with DFO and other iron chelators for treatment of tumors with invasive potential.
authors.affiliation: Center of Hygiene Assessment and Research, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Liu
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Cui
authors.forename: Miao
authors.initials: M
authors.lastname: Shi
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Chen
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003676:Deferoxamine / Q000633:toxicity*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009861:Onium Compounds / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017262:Siderophores / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005419:Flavonoids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009861:Onium Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D017262:Siderophores; C007517:diphenyleneiodonium; D019255:NADPH Oxidases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D003676:Deferoxamine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one