Jo M, Lester RD, Montel V, Eastman B, Takimoto S, Gonias SL
Reversibility of epithelial-mesenchymal transition (EMT) induced in breast cancer cells by activation of urokinase receptor-dependent cell-signaling. [JOURNAL ARTICLE]
J Biol Chem 2009 Jun 22.
Hypoxia induces expression of the urokinase receptor (uPAR) and activates uPAR-dependent cell-signaling in cancer cells. This process promotes epithelial-mesenchymal transition(EMT). uPAR over-expression in cancer cells also promotes EMT. In this study, we tested whether uPAR may be targeted to reverse cancer cell EMT. When MDA-MB 468 breast cancer cells were cultured in 1% O(2), uPAR expression increased, as anticipated. Cell-cell junctions were disrupted, vimentin expression increased, and e-cadherin was lost from cell surfaces, indicating EMT. Transferring these cells back to 21% O(2) decreased uPAR expression and reversed the signs of EMT. In uPAR over-expressing MDA-MB 468 cells, EMT was reversed by silencing expression of endogenously-produced urokinase-type plasminogen activator (uPA), which is necessary for uPAR-dependent cell-signaling, or by targeting uPAR-activated cell-signaling factors, including phosphatidylinositol 3-kinase, Src family kinases, and extracellular signal-regulated kinase. MDA-MB 231 breast cancer cells express high levels of uPA and uPAR and demonstrate mesenchymal cell morphology under normoxic culture conditions (21% O(2)). Silencing uPA expression in MDA-MB-231 cells decreased expression of vimentin and Snail, and induced changes in morphology characteristic of epithelial cells. These results demonstrate that uPAR-initiated cell-signaling may be targeted to reverse EMT in cancer.
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