title: c-Src regulates constitutive and EGF-mediated VEGF expression in pancreatic tumor cells through activation of phosphatidyl inositol-3 kinase and p38 MAPK.
abstract: OBJECTIVE
  Multiple signaling proteins may be aberrantly activated and/or overexpressed in pancreatic tumors, including the nonreceptor protein tyrosine kinase Src. The goal of this study was to determine the role of Src in regulating VEGF expression and angiogenic potential in pancreatic cancer cell lines.
  
  
  METHODS
  Src activity was inhibited using the Src family kinase selective inhibitor PP2, and c-Src expression was down-regulated via siRNA. The activities of downstream signaling molecules phosphatidyl inositol 3'-kinase (PI3K) and p38 mitogen-activated protein kinase (MAPK) were disrupted via selective inhibitors. In vivo angiogenesis was assessed through the use of a gel-foam assay.
  
  
  RESULTS
  Inhibition of Src activity or expression decreases both constitutive and EGF-induced VEGF production. Both the PI3K/Akt and p38 MAPK pathways are activated in a Src family kinase-dependent fashion on EGF-R activation and are important for EGF-mediated VEGF production in pancreatic cancer cells. Additionally, media from Src-inhibited L3.6pl cells fail to promote angiogenesis into gel foams implanted subcutaneously into mice, whereas media from control cells promote a robust angiogenic response.
  
  
  CONCLUSIONS
  Src activity contributes to constitutive and EGF-induced VEGF expression and angiogenic potential in pancreatic cancer cells. Therefore, Src may be a viable target for antiangiogenesis therapy in pancreatic cancer.
authors.affiliation: University of Texas MD Anderson Cancer Center, Department of Cancer Biology, Houston, TX 77054, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Summy
authors.forename: Jose G
authors.initials: JG
authors.lastname: Trevino
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Baker
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases; C000631346:CSK protein, human