title: AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells.
abstract: Insulin-like growth factor I receptor (IGF-IR) is frequently overexpressed in several types of human malignancy and is associated with invasion and metastasis of tumor cells. Recently, IGF-IR expression was reported to be up-regulated in the human pancreatic cancer cell line PANC-1 when cells were stably transfected with active Src. The downstream targets of Src that lead to the up-regulation of IGF-IR expression were previously unknown. We demonstrate here that AKT regulates IGF-IR expression in PANC-1 and AsPC-1 cells. Cells transfected with active Src exhibited significantly more IGF-IR protein compared with vector-transfected cells. Overexpression of wild-type or constitutively active AKT (i.e., AKT1 or AKT2) also resulted in elevated IGF-IR expression. IGF-IR protein levels were higher in cells transfected with constitutively active AKT than in cells transfected with active Src. In vitro kinase assays showed that AKT kinases are activated by active Src and inhibited by dominant negative Src or the tumor suppressor PTEN. Furthermore, AKT-induced IGF-IR expression was down-regulated by dominant-negative Src or PTEN. In addition, cells transfected with activated AKT in the presence of IGF-I were shown to have enhanced invasiveness compared with control cells. These data provide evidence for a link between AKT signaling and the regulation of IGF-IR expression and demonstrate that active AKT promotes the invasiveness of pancreatic cancer cells through the up-regulation of IGF-IR expression.
authors.affiliation: Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors.forename: S
authors.initials: S
authors.lastname: Tanno
authors.forename: S
authors.initials: S
authors.lastname: Tanno
authors.forename: Y
authors.initials: Y
authors.lastname: Mitsuuchi
authors.forename: D A
authors.initials: DA
authors.lastname: Altomare
authors.forename: G H
authors.initials: GH
authors.lastname: Xiao
authors.forename: J R
authors.initials: JR
authors.lastname: Testa
mesh_terms: D015153:Blotting, Western; D004274:DNA, Recombinant; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D004274:DNA, Recombinant; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D017526:Receptor, IGF Type 1; D019061:src-Family Kinases; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human