title: Influence of Pi3-K and PKC activity on 99mTc-(V)-DMSA uptake: correlation with tumour aggressiveness in an in vitro malignant glioblastoma cell line model.
abstract: OBJECTIVE
  Intensive proliferation and a high degree of migration and invasion are characteristic features of malignant glioblastomas, associated with a poor prognosis. Phosphatidylinositol-3-kinase (Pi3-K) and protein kinase C (PKC) are two phosphorylated proteins involved in glioblastoma cell progression. Phosphorylated focal adhesion protein kinase (FAK) has also been reported to be involved in tumour progression. In a recent study, we demonstrated a correlation between phosphorylated FAK, proliferation rate and 99mTc-(V)-dimercaptosuccinate [(V)-DMSA] uptake. We hypothesised that 99mTc-(V)-DMSA could be a potential imaging agent to evaluate glioblastoma aggressiveness. The aim of the present study was to assess the relationship between 99mTc-(V)-DMSA incorporation rate and modulation of Pi3-K and PKC activity.
  
  
  METHODS
  Proliferation, migration and invasion capacities in the presence of protein kinase modulators-staurosporine (PKC inhibitor), 4-phorbol 12-myristate 13-acetate (PMA; PKC activator) and LY294002 (Pi3-K inhibitor)-were correlated with 99mTc-(V)-DMSA cell accumulation in an in vitro model of several malignant glioma cells: G111 (grade II), U-87-MG (grade III) and G152 (grade IV).
  
  
  RESULTS
  In all cell lines tested, LY294002 and staurosporine treatment inhibited cell proliferation, migration and invasion. In contrast, treatment with PMA stimulated tumour aggressiveness. 99mTc-(V)-DMSA uptake was strongly correlated with the % of cellular proliferation (r=0.8462) and the % of cellular migration (r=0.9081), and to a lesser extent with the % of cellular invasion (r=0.7761).
  
  
  CONCLUSIONS
  Our results clearly demonstrated that 99mTc-(V)-DMSA reflects Pi3-K and PKC activity and is correlated with tumour aggressiveness. 99mTc-(V)-DMSA could be a reliable in vivo marker providing additional information on the biological status of malignant glioblastoma.
authors.affiliation: Laboratory of Biophysics and Radiopharmaceuticals, Research Group EA 3063 Cellular Survival and Adhesion in Tumors and Grafts, Faculty of Medicine Jacques Lisfranc, University of Saint-Etienne, France. nathalie.lejeune@univ-st-etienne.fr
authors.forename: Nathalie
authors.initials: N
authors.lastname: Le Jeune
authors.forename: Nathalie
authors.initials: N
authors.lastname: Perek
authors.forename: Francis
authors.initials: F
authors.lastname: Dubois
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013223:Statistics as Topic; D019783:Technetium Tc 99m Dimercaptosuccinic Acid / Q000493:pharmacokinetics*
chemical_list: D019275:Radiopharmaceuticals; D019783:Technetium Tc 99m Dimercaptosuccinic Acid; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C