title: Lipocalin 2 antagonizes the proangiogenic action of ras in transformed cells.
abstract: Lipocalin 2 is an iron-binding secreted protein that converts embryonic kidney mesenchyme to epithelia. Previously, we reported that lipocalin 2 could revert 4T1-ras-transformed mesenchymal tumor cells to a more epithelial phenotype, increase E-cadherin expression, and suppress cell invasiveness in vitro and in vivo, indicating that lipocalin 2 is a metastasis suppressor. Here, we show that lipocalin 2 can suppress the ras-induced expression of vascular endothelial growth factor in 4T1 cells via down-regulation of ras mitogen-activated protein kinase and ras phosphatidylinositol-3-kinase signaling. In addition, the expression of thrombospondin-1 (an antiangiogenic molecule) was increased in tumors formed by 4T1-ras cells into which lipocalin 2 was stably introduced. Tumor angiogenesis, assessed via an intradermal tumor angiogenesis assay, was also suppressed by lipocalin 2. We also show that caveolin-1 is a critical mediator of this activity. These data provide new insights into the action of lipocalin 2 and raise the possibility that the administration of lipocalin 2 may be useful for inhibiting tumor angiogenesis, in addition to suppressing tumor metastasis, in cancers which show ras activation.
authors.affiliation: Renal Division and Center for Study of the Tumor Microenvironment, Department of Medicine, Beth Israel Deaconess Medical, 330 Brookline Avenue, RW 563, Boston, MA 02215, USA.
authors.forename: Shivalingappa
authors.initials: S
authors.lastname: Venkatesha
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Hanai
authors.forename: Pankaj
authors.initials: P
authors.lastname: Seth
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.forename: Vikas P
authors.initials: VP
authors.lastname: Sukhatme
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000502:physiology*; D000818:Animals; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D015536:Down-Regulation; D006801:Humans; D007501:Iron / Q000378:metabolism / Q000494:pharmacology; D000071068:Lipocalin-2; D054834:Lipocalins; D051379:Mice; D008807:Mice, Inbred BALB C; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000209:Acute-Phase Proteins; D051242:Caveolin 1; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D007501:Iron; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins