title: c-Src inactivation reduces renal epithelial cell-matrix adhesion, proliferation, and cyst formation.
abstract: c-Src is a non-receptor tyrosine kinase whose activity is induced by phosphorylation at Y418 and translocation from the cytoplasm to the cell membrane. Increased activity of c-Src has been associated with cell proliferation, matrix adhesion, motility, and apoptosis in tumors. Immunohistochemistry suggested that activated (pY(418))-Src activity is increased in cyst-lining autosomal dominant polycystic kidney disease (ADPKD) epithelial cells in human and mouse ADPKD. Western blot analysis showed that SKI-606 (Wyeth) is a specific inhibitor of pY(418)-Src without demonstrable effects on epidermal growth factor receptor or ErbB2 activity in renal epithelia. In vitro studies on mouse inner medullary collecting duct (mIMCD) cells and human ADPKD cyst-lining epithelial cells showed that SKI-606 inhibited epithelial cell proliferation over a 24-h time frame. In addition, SKI-606 treatment caused a striking statistically significant decrease in adhesion of mIMCD and human ADPKD to extracellular collagen matrix. Retained viability of unattached cells was consistent with a primary effect on epithelial cell anchorage dependence mediated by the loss of extracellular matrix (ECM)-attachment due to α(2)β(1)-integrin function. SKI-606-mediated attenuation of the human ADPKD hyperproliferative and hyper-ECM-adhesive epithelial cell phenotype in vitro was paralleled by retardation of the renal cystic phenotype of Pkd1 orthologous ADPKD heterozygous mice in vivo. This suggests that SKI-606 has dual effects on cystic epithelial cell proliferation and ECM adhesion and may have therapeutic potential for ADPKD patients.
authors.affiliation: Division of Nephrology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Justine
authors.initials: J
authors.lastname: Elliott
authors.forename: Nadezhda N
authors.initials: NN
authors.lastname: Zheleznova
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Wilson
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation; D016891:Polycystic Kidney, Autosomal Dominant / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D000814:Aniline Compounds; D003094:Collagen; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D016392:Proto-Oncogene Proteins pp60(c-src); D011804:Quinolines; D050396:TRPP Cation Channels; C471992:bosutinib