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Deferoxamine promotes MDA-MB-231 cell migration and invasion through increased ROS-dependent HIF-1α accumulation
Yiping Liu1, Yongfeng Cui, Miao Shi
1Center of Hygiene Assessment and Research, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing, China.
Background/Aim:
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.
Conclusion:
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.
