title: Novel expression of N-cadherin elicits in vitro bladder cell invasion via the Akt signaling pathway.
abstract: Novel N-cadherin expression has been linked to the invasive phenotype in bladder tumors yet a primary role for N-cadherin in invasion has not been defined in this model. To address this, N-cadherin was stably transfected into E-cadherin expressing bladder carcinoma cells. This resulted in an enhanced invasive capacity in in vitro assays that was blocked by incubation with an N-cadherin function-blocking antibody in a dose-dependent manner. Analysis of the signaling pathway(s) implicated in N-cadherin-mediated invasion in bladder carcinoma cell lines revealed no correlation between MAPK signaling and invasion, in the presence or absence of fibroblast growth factor 2. Also, while MAPK and p38 kinase inhibitors did not alter the invasive behavior of these cells, an increase in the phosphorylation of Akt at serine-473 was detected in N-cadherin transfectants, suggestive of N-cadherin-mediated Akt activation in bladder cell invasion. Incubation of N-cadherin transfectants with either PI3 kinase or Akt inhibitors resulted in a significant decrease in the invasive capacity of these cells. Exposure of cells to PP2, a src family kinase inhibitor, also decreased the invasive potential of N-cadherin transfectants and resulted in reduced phosphorylation of Akt. The involvement of Akt signaling in bladder cell invasion was also supported by the inhibition of bladder cell invasion by cells constitutively expressing an activated Akt kinase, using the PI3 kinase and Akt inhibitors and PP2. These results suggest that activation of PI3/AKT kinase following N-cadherin expression contributes to the increased invasive potential of bladder carcinoma cells.
authors.affiliation: Cell and Molecular Biology Laboratory, RE Wise MD Research and Education Institute, 31 Mall Road, Burlington, MA 01805, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Rieger-Christ
authors.forename: Peter
authors.initials: P
authors.lastname: Lee
authors.forename: Ralph
authors.initials: R
authors.lastname: Zagha
authors.forename: Monika
authors.initials: M
authors.lastname: Kosakowski
authors.forename: Alireza
authors.initials: A
authors.lastname: Moinzadeh
authors.forename: John
authors.initials: J
authors.lastname: Stoffel
authors.forename: Avri
authors.initials: A
authors.lastname: Ben-Ze'ev
authors.forename: John A
authors.initials: JA
authors.lastname: Libertino
authors.forename: Ian C
authors.initials: IC
authors.lastname: Summerhayes
mesh_terms: D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D002999:Clone Cells; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007797:Laminin / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D015820:Cadherins; D002867:Chromones; D003094:Collagen; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007797:Laminin; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D012694:Serine; C059485:matrigel; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one