Nesis, can be a major one (6-16). The activation of the AKT pathway promotes the transition from anaplastic astrocytoma to glioblastoma (17), is correlated to histological IL-27, Human (CHO, His) malignant evolution and is actually a negative prognosis element (18,19). Furthermore, the intrinsic radioresistance of glioblastoma is correlated with activation levels of AKT (15) as well as the activation of AKT confers them radioresistance (7). In the course of MKK6 Protein Formulation carcinogenesis, the activation on the AKT pathway mostly occurs by the acquire of activity of upstream activators including EGFR (12,20-23), or by the loss of activity of an upstream inhibitor, PTEN (7,24,25). PTEN dephosphorylates PIP3 into PIP2 through its lipid-phosphatase activity and decreases the amount of the phosphorylated active form of AKT (24,26). During gliomagenesis, the AKT pathway can also be often activated (27,28) and PTEN disrupted (29-31). Consequently the inhibition of AKT by either PTEN re-expression or PI3K inhibitors impairs DNA repair and radiosensitizes glioblastoma (13,15,32,33). Telomerase is really a certain reverse transcriptase that elongates the telomeres, enables limitless proliferation of cancer cells and is at the moment connected to their radioresistance (34-36). Consequently telomerase inhibition shortens telomeres and radiosensitizes cells (37). Telomerase is reactivated in 80-100 of glioblastomas (38) and its levels are correlated using the pathological grade and also the prognosis from the tumor (38-42). This suggests that telomerase may also intervene in the radioresistance of glioblastomas by either triggering telomere maintenance and/or chromosome healing (43). Consequently telomere targeting or telomerase inhibition radiosensitizes glioblastoma cell lines (11,44-46). The evidenced importance of telomerase activity in the biology along with the clinical outcomes of gliomas points out this enzyme as an appropriate therapeutic target for the radiosensitization of glioblastomas. Interestingly, the telomerase activity is directly regulated by AKT either by phosphorylation in the hTERT subunit (47) or by both post-translational and transcriptional mechanisms (48,49). Moreover, ionizing radiation increases the telomerase activity in various cancer cell lines (35,50-53) by a post-translational mechanism implicating PI3K/AKT pathway (54). But nonetheless, the upregulation of telomerase activity induced by ionizing radiation in glioblastoma cells (46) remains to be linked to PTEN/PI3-kinase/AKT pathway.MILLET et al: REGULATION OF TELOMERASE ACTIVITY IN IRRADIATED HIGH-GRADE GLIOMASAs each PI3K/AKT and telomerase seem to be potential targets for cancer therapy and radio-sensitization of brain cancers (five,11,15,16,43,45,55-57), we decided to study the links between telomerase activity and AKT pathway in human glioblastomas as a way to challenge the concept of a `killing two birds with 1 stone’ radio-sensitizing technique. Therefore, we evaluated the effects of a specific PI3K inhibitor (Ly-294002) (58) within the radioresponse of two telomerase constructive high-grade glioma cell lines: CB193 (grade III WHO) a PTEN null one (59,60) plus a T98G (grade IV WHO) a PTEN harbouring one particular (61,62). Supplies and solutions Cell culture. Human malignant glioma cell lines CB193 (astrocytoma, grade III) (59) and T98G (glioblastoma multiforme, grade IV) (61,62) were kindly supplied by Dr G. Gras (CEA, France). Cultures (5×105 cells/flask) had been maintained in DMEM medium (Life Technologies, Grand Island, NY, USA) supplemented with 10 fetal bovine serum (Life Technologies),.