title: Caspase-9 transduction overrides the resistance mechanism against p53-mediated apoptosis in U-87MG glioma cells.
abstract: OBJECTIVE
  Conflicting reports have been published with regard to the relationship between the efficacy of p53 gene therapy and the p53 status of gliomas. In this study, we evaluated whether U-87MG glioma cells harboring wild-type p53 and U251 and U-373MG glioma cells harboring mutated p53 demonstrate different sensitivities to p53-induced apoptosis. In addition, we tested whether transduction of Bax or caspase-9, which are downstream components of p53-induced apoptosis, can override the resistance mechanism of U-87MG cells to apoptosis.
  
  
  METHODS
  We transduced U-87MG, U251, and U-373MG glioma cells with p53, Bax, or caspase-9 genes via adenovirus (Adv) vectors, to induce the same level of respective proteins, and evaluated the degree of apoptosis.
  
  
  RESULTS
  U-87MG cells were highly resistant to Adv for p53 (Adv-p53)-mediated apoptosis, whereas U251 and U-373 cells underwent extensive apoptosis after Adv-p53 infection. In U-87MG cells, the elevation of Bax and Fas was not as marked as that observed in U251 and U-373MG cells after Adv-p53 infection. Endogenous expression of Bcl-XL and Bcl-2 in U-87MG cells was greater than that in U251 and U-373MG cells. U-87MG cells were more resistant to Bax-mediated apoptosis than were U251 or U-373MG cells. In contrast, U-87MG cells were more sensitive to caspase-9-mediated apoptosis than were U251 or U-373MG cells, suggesting that transduction of caspase-9 may override the resistance mechanism of U-87MG to p53-mediated apoptosis.
  
  
  CONCLUSIONS
  These results demonstrate that proapoptotic function induced by p53 transduction in U-87MG cells was repressed at several steps and that induction of caspase-9 may circumvent this resistance mechanism.
authors: Department of Molecular Biotherapy Research, Cancer Institute, Tokyo, Japan. shinoura-k@komagome-hospital.bunkyo.tokyo.jp
authors: N
authors: N
authors: Shinoura
authors: S
authors: S
authors: Sakurai
authors: A
authors: A
authors: Asai
authors: T
authors: T
authors: Kirino
authors: H
authors: H
authors: Hamada
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000494:pharmacology*; D004351:Drug Resistance; D018014:Gene Transfer Techniques; D005910:Glioma / Q000473:pathology / Q000503:physiopathology*; D009154:Mutation / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
chemical_list: D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D053453:Caspase 9; D020169:Caspases