title: Knock-down of Pdcd4 stimulates angiogenesis via up-regulation of angiopoietin-2.
abstract: The tumor suppressor Pdcd4 is involved in multiple pathways. Considering its biological action conflicting data in the literature exist and, consequently, our own studies point to a cell type specific action of Pdcd4. In the present study, using several Pdcd4 knock down cell lines we succeeded to identify angiopoietin-2 (Ang-2) as a gene up-regulated on the mRNA and protein level. The subsequent enhanced peptide secretion forced wild type Bon-1 cells in a neoplastic direction demonstrated by increased proliferation and colony formation while cell adhesion was decreased. Most likely, the stimulation of Ang-2 is in part mediated by increased activation of AP-1 but different signal transduction pathways may also be involved since we found opposite activation of PI3K/Akt/mTOR and MAPK7ERK pathways (both known to regulate in Ang-2 expression). Ang-2 is a modulator of vascular remodeling. Therefore, we analyzed the effect of supernatants from Pdcd4 knock-down cell lines on endothelial cells. Again, we detected reduced cell adhesion and increased colony formation. Probably, the most impressive effect was described on tube formation in a model for angiogenesis. Tube length and junctions of endothelial cells treated with conditioned medium from Pdcd4 knock-down cells were considerably increased. Both, up-regulation of Ang-2 and down-regulation of Pdcd4 are described for many tumors. However, this is the first study showing a direct impact of Pdcd4 on Ang-2 levels and, thereby, angiogenesis. Our data suggest a completely new mechanism for Pdcd4 to act as a tumor suppressor rendering Pdcd4 an attractive target for new therapeutic strategies in cancer treatment.
authors.affiliation: Department of Gastroenterology, University of Marburg, Baldingerstrasse, Marburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Krug
authors.forename: Johannes
authors.initials: J
authors.lastname: Huth
authors.forename: Friederike
authors.initials: F
authors.lastname: Göke
authors.forename: Malte
authors.initials: M
authors.lastname: Buchholz
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Gress
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Göke
authors.forename: Brigitte
authors.initials: B
authors.lastname: Lankat-Buttgereit
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
chemical_list: D042702:Angiopoietin-2; D051017:Apoptosis Regulatory Proteins; D017077:Culture Media, Conditioned; C114487:PDCD4 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins