Figure 5. Iron chelators regulate the epithelial-to-mesenchymal transition (EMT) and molecular motors involved in cancer cell migration and metastasis.

Non-canonical activation of TGF-β signaling promotes tumor progression, EMT and metastasis via SMAD, MAPK and PI3K/AKT pathways that up-regulate mesenchymal-associated transcription factors (e.g., Snail, Slug, Twist and ZEB) and repress E-cadherin expression. The Wnt signaling pathway also regulates EMT through its inhibition of GSK3β-mediated degradation of β-catenin, Snail and Slug. TGF-β can also activate Rho/ROCK/MLC signaling to drive dynamic actin reorganization required for metastasis. Iron chelators have been demonstrated to inhibit the EMT and metastasis by maintaining expression of E-cadherin and β-catenin at cell membranes, and may also mediate these effects through regulation of other upstream cascades (see text for more details). Molecules negatively regulated by iron chelators are indicated by red boxes, and those positively regulated are indicated by green boxes. Solid boxes indicate direct evidence for modulation by iron chelators, while dashed boxes indicate potential indirect modulation, e.g., through chelator-mediated up-regulation of NDRG1.