title: Radiation-induced upregulation of telomerase activity escapes PI3-kinase inhibition in two malignant glioma cell lines.
abstract: Tumor relapse after radiotherapy is a great concern in the treatment of high-grade gliomas. Inhibition of the PI3-kinase/AKT pathway is known to radiosensitize cancer cells and to delay their DNA repair after irradiation. In this study, we show that the radiosensitization of CB193 and T98G, two high-grade glioma cell lines, by the PI3K inhibitor LY294002, correlates with the induction of G1 and G2/M arrest, but is inconsistently linked to a delayed DNA double-strand break (DSBs) repair. The PI3K/AKT pathway has been shown to activate radioprotective factors such as telomerase, whose inhibition may contribute to the radiosensitization of cancer cells. However, we show that radiation upregulates telomerase activity in LY-294002-treated glioma cells as well as untreated controls, demonstrating a PI3K/AKT-independent pathway of telomerase activation. Our study suggests that radiosensitizing strategies based on PI3-kinase inhibition in high-grade gliomas may be optimized by additional treatments targeting either telomerase activity or telomere maintenance.
authors.affiliation: CEA, DSV-IRCM-SCSR, Laboratory of Radiopathology, UMR 967, F-92260 Fontenay‑aux‑Roses, France. pascal.millet@univ-amu.fr
authors.forename: P
authors.initials: P
authors.lastname: Millet
authors.forename: C
authors.initials: C
authors.lastname: Granotier
authors.forename: O
authors.initials: O
authors.lastname: Etienne
authors.forename: F D
authors.initials: FD
authors.lastname: Boussin
mesh_terms: D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D059565:G2 Phase Cell Cycle Checkpoints; D005910:Glioma / Q000532:radiotherapy*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism* / Q000528:radiation effects; D015854:Up-Regulation
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011838:Radiation-Sensitizing Agents; D019098:Telomerase; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one