GY 43: 375-382,Radiation-induced upregulation of telomerase activity escapes PI3-kinase inhibition in two malignant glioma cell linesP. MILLET1,five, C. GRANOTIER1-4, O. ETIENNE1-4 and F.D. BOUSSIN1-CEA, DSV-IRCM-SCSR, Laboratory of Radiopathology, UMR 967, F-92260 Fontenay-aux-Roses; INSERM, UMR 967, F-92260 Fontenay-aux-Roses; 3Univ Paris Diderot, Sorbonne Paris Cit? UMR 967, F-92260 Fontenay-aux-Roses; 4Univ Paris-Sud, UMR 967, F-92260 Fontenay-aux-Roses, France Received March 10, 2013; Accepted April 19, 2013 DOI: 10.3892/ijo.2013.Abstract. Tumor relapse soon after radiotherapy can be a fantastic concern in the remedy of high-grade gliomas. Inhibition on the PI3-kinase/AKT pathway is recognized to radiosensitize cancer cells and to delay their DNA repair following irradiation. Within this study, we show that the radiosensitization of CB193 and T98G, two high-grade glioma cell lines, by the PI3K inhibitor LY294002, correlates using the induction of G1 and G2/M arrest, but is inconsistently linked to a delayed DNA doublestrand break (DSBs) repair. The PI3K/AKT pathway has been shown to activate radioprotective things such as telomerase, whose inhibition could contribute to the radiosensitization of cancer cells. Having said that, we show that radiation upregulates telomerase activity in LY-294002-treated glioma cells also as untreated controls, demonstrating a PI3K/AKT-independent pathway of telomerase activation. Our study suggests that radiosensitizing techniques depending on PI3-kinase inhibition in high-grade gliomas might be optimized by further treatment options targeting either telomerase activity or telomere maintenance. Introduction Glioblastoma multiforme (GBM) may be the most typical and also the most aggressive brain tumor having a median survival of only 15 months (1,two). In spite of conjugated surgery, radiotherapy and chemotherapy most individuals die inside the initially year of diagnosis (3,four). The molecular mechanisms implicated inside the resistance of glioblastoma to chemotherapies and radiotherapies overlap with these implicated in oncogenesis (5).2,6-Di(1-pyrazolyl)pyridine In stock Amongst those, the PI3K/AKT pathway which is implicated inCorrespondence to: Dr Pascal Millet,Aix-Marseille Univ, CNRS, NICN, UMR 7259, North Healthcare Faculty, CS 811, 51 Bd Pierre Dramard, 13344 Marseille Cedex 15, France E-mail: [email protected] address:Important words: telomerase, radiation, PI3-kinase, radiosensitization,glioma, glioblastomaregulation of cell proliferation, cell cycle, survival, apoptosis, migration and angiogenesis, is usually a major a single (6-16).(S)-2-Amino-2,4-dimethylpentan-1-ol Chemical name The activation in the AKT pathway promotes the transition from anaplastic astrocytoma to glioblastoma (17), is correlated to histological malignant evolution and is often a damaging prognosis aspect (18,19).PMID:33674962 Additionally, the intrinsic radioresistance of glioblastoma is correlated with activation levels of AKT (15) and the activation of AKT confers them radioresistance (7). In the course of carcinogenesis, the activation on the AKT pathway mostly happens by the get of activity of upstream activators like 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 kind of AKT (24,26). In the course of gliomagenesis, the AKT pathway is also frequently 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.