Ced increase in telomerase activity in irradiated cells, ruling out a part in the PI3K/AKT pathway inside the radiation-induced upregulation of telomerase activity in our model. Discussion The PI3-kinase/AKT pathway is far more and more regarded as an interesting therapeutic target for the radiosensitization of glioblastoma, however the mechanisms of radiosensitization resulting from the inhibition of the PI3K/AKT pathway stay still unclear. Its inhibition has been reported to impair DNA repair in glioblastoma cells following ionizing radiation, therebyblocking cell cycle progression and cell death (13). In this study, we have shown that the radiosensitization of two glioma cell lines by the PI3K inhibitor, Ly-294002, correlated with the induction of G1 and G2/M arrests, but was inconsistently linked to a delayed DSBs repair. The PI3K/AKT pathway has been also shown to activate radioprotective things which include telomerase, which inhibition could contribute to radiosensitization (11,44-46). Even so, we’ve got shown that radiation upregulated telomerase activity in Ly-294002-treated glioma cells also as in untreated p70S6K Inhibitor Species controls, irrespective of their PTEN status, evidencing a PI3K/AKT independent pathway of telomerase activation. High-grade gliomas are known for their inter- and intra-patient heterogeneity. They express diversely telomerase activity and telomerase sub-units, but this expression is strongly correlated to their progression in malignancy and also a poor clinical outcome (38,39,42,69-71). Our study tends to indicate that the strategy of radiosensitization of high-grade gliomas ought to combine different approaches and should be adapted for the individual characteristics with the tumor particularly relating to their telomerase status. A lot of earlier reports have shown that inhibition with the PI3K/AKT pathways radiosensitize gliomas (13,15,32,33), consistently with the activation of PI3K/AKT conferring PKCθ Activator Storage & Stability radioresistance (7). Ionizing radiation has been shown to boost Akt phosphorylation in a variety of cell lines like gliomas (32,72). Nevertheless, we didn’t locate any radiationincrease of AKT phosphorylation in our two glioma cells, regularly using the study by Li et al (32) showing that AKT phosphorylation occurred only within a subset of glioblastoma cells. Ly-294002 induced a G1 arrest in both CB193 and T98G cells in accordance together with the significance in the PI3K/AKT signaling for G1/S transition (73-75). Furthermore, as previously reported in other cell lines (76,77), inhibition from the PI3K/ AKT pathway resulted in an accumulation in G2/M phase, but only right after irradiation. Inhibition of the PI3K pathway has been shown to impair DNA repair just after ionizing radiation, suggesting that the blocking at the G2/M transition and subse-MILLET et al: REGULATION OF TELOMERASE ACTIVITY IN IRRADIATED HIGH-GRADE GLIOMASquent cell death may well result from an inhibition of DSB repair (13,78). Having said that, this is not fully sustained by our present study showing that the G2/M arrest was correlated with a delay in DSBs repair only in T98G but not in CB193 cells, immediately after the treatment with Ly-294002. Activation of AKT has been also shown to market G2/M transition by means of the activation of downstream molecules including cyclin B associated kinase, NF-Y, Chk1 and FOXO3A (79-81). Our information suggest that beside feasible inhibition of DNA repair based on the cellular context, Ly-294002 inhibits the signaling pathway essential to pass the G2/M checkpoint independently of DNA repair completion in irrad.