title: Retroviral expression of a kinase-defective IGF-I receptor suppresses growth and causes apoptosis of CHO and U87 cells in-vivo.
abstract: BACKGROUND
  Phosphatidylinositol-3,4,5-triphosphate (PtdInsP3) signaling is elevated in many tumors due to loss of the tumor suppressor PTEN, and leads to constitutive activation of Akt, a kinase involved in cell survival. Reintroduction of PTEN in cells suppresses transformation and tumorigenicity. While this approach works in-vitro, it may prove difficult to achieve in-vivo. In this study, we investigated whether inhibition of growth factor signaling would have the same effect as re-expression of PTEN.
  
  
  METHODS
  Dominant negative IGF-I receptors were expressed in CHO and U87 cells by retroviral infection. Cell proliferation, transformation and tumor formation in athymic nude mice were assessed.
  
  
  RESULTS
  Inhibition of IGF-IR signaling in a CHO cell model system by expression of a kinase-defective IGF-IR impairs proliferation, transformation and tumor growth. Reduction in tumor growth is associated with an increase in apoptosis in-vivo. The dominant-negative IGF-IRs also prevented growth of U87 PTEN-negative glioblastoma cells when injected into nude mice. Injection of an IGF-IR blocking antibody alphaIR3 into mice harboring parental U87 tumors inhibits tumor growth and increases apoptosis.
  
  
  CONCLUSIONS
  Inhibition of an upstream growth factor signal prevents tumor growth of the U87 PTEN-deficient glioma to the same extent as re-introduction of PTEN. This result suggests that growth factor receptor inhibition may be an effective alternative therapy for PTEN-deficient tumors.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. lseely@producthealth.com
authors.forename: B Lynn
authors.initials: BL
authors.lastname: Seely
authors.forename: Goli
authors.initials: G
authors.lastname: Samimi
authors.forename: Nicholas J G
authors.initials: NJ
authors.lastname: Webster
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D016543:Central Nervous System Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006224:Cricetinae; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D006131:Growth Inhibitors; D011518:Proto-Oncogene Proteins; D017526:Receptor, IGF Type 1; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt