Role of phosphoinositide-3-kinase (PI3K)/Akt signaling in apoptosis regulation of neuroectodermal tumors
Auch gedruckt in der BibliothekZ: J-H 11.850; W: W-H 11.350
Ressourcen- / MedientypDissertation, Text
Datum der Freischaltung2008-06-06
Inhibition of PI3K significantly sensitized glioblastoma cells for death-inducing ligands, as well as for different anticancer drugs in a synergistic manner, whereas inhibition of mTOR or MEK did not significantly alter the sensitivity of glioblastoma cells for TRAIL- or Doxorubicin-induced apoptosis. In addition, LY294002 cooperates with TRAIL or Doxorubicin to suppress colony formation demonstrating an effect also on longterm survival. Similarly, genetic knockdown of PI3K primes glioblastoma cells for TRAIL- or Doxorubicin-mediated apoptosis. Analysis of apoptosis pathways revealed that PI3K inhibition collaborates with TRAIL or Doxorubicin to trigger mitochondrial membrane permeabilization, caspase activation and caspase-dependent apoptosis. Importantly, PI3K inhibition by LY294002 sensitizes primary glioblastoma cells for TRAIL- or chemotherapy-induced cell death. Additionally, this study provides evidence that phosphorylation of Akt, S6 ribosomal protein and ERK occurs in a large proportion of primary neuroblastoma. Importantly, phosphorylation of Akt was identified as a novel prognostic indicator of decreased event-free or overall survival. Akt activity significantly correlated with parameters of aggressive disease. Experiments in neuroblastoma cell lines revealed that activation of PI3K signaling by IGF-1 significantly inhibited TRAIL- or chemotherapy-induced apoptosis. Accordingly, pharmacological inhibition of PI3K completely reversed the ability of IGF-1 to rescue neuroblastoma cells from apoptosis. Thus, by demonstrating that Akt activity correlates with poor prognosis in primary neuroblastoma in vivo and with apoptosis resistance in vitro, and that inhibition of PI3K significantly enhanced both death receptor- and anticancer drug-induced cell death in glioblastoma cells, these findings highlight PI3K/Akt signaling as a crucial mediator of apoptosis in neuroectodermal tumors.
LizenzStandard (Fassung vom 03.05.2003)
TNF-related apoptosis-including ligand