Lipocalin 2 diminishes invasiveness and metastasis of Ras-transformed cells.
Lipocalin 2, an iron-siderophore-binding protein, converts embryonic kidney mesenchyme to epithelia. We found that lipocalin 2 could also convert 4T1-Ras-transformed mesenchymal tumor cells to an epithelial phenotype, increase E-cadherin expression, and suppress cell invasiveness in vitro and tumor growth and lung metastases in vivo. The Ras-MAPK pathway mediated the epithelial to mesenchymal transition in part by increasing E-cadherin phosphorylation and degradation. Lipocalin 2 antagonized these effects at a point upstream of Raf activation. Lipocalin 2 action was enhanced by iron-siderophore. These data characterize lipocalin 2 as an epithelial inducer in Ras malignancy and a suppressor of metastasis.
Hanai
Jun-ichi
J
Division of Nephrology, Department of Medicine and Center for Study of the Tumor Microenvironment, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Mammoto
Tadanori
T
Seth
Pankaj
P
Mori
Kiyoshi
K
Karumanchi
S Ananth
SA
Barasch
Jonathan
J
Sukhatme
Vikas P
VP
D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D007501:Iron / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins; D020935:MAP Kinase Signaling System / Q000502:physiology; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D000209:Acute-Phase Proteins; D015820:Cadherins; D004791:Enzyme Inhibitors; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins; D007501:Iron; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; D018631:ras Proteins