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oai:recercat.cat:2445/330052025-12-05T14:37:45Zcom_2072_1057col_2072_478861col_2072_478916col_2072_478917

TP53 induced glycolysis and apoptosis regulator (TIGAR) knockdown results in radiosensitization of glioma cells Peña Rico, Miguel A. Calvo-Vidal, María Nieves Vilallonga Planells, Ruth Martínez Soler, Fina Giménez Bonafé, Pepita Navarro i Sabaté, Àurea Tortosa i Moreno, Avelina Bartrons Bach, Ramon Manzano Cuesta, Anna Glioma Proteïnes supressores de tumors Gliomas Tumor suppressor protein Background and purpose: The TP53 induced glycolysis and apoptosis regulator (TIGAR) functions to lower fructose-2,6-bisphosphate (Fru-2,6-P2) levels in cells, consequently decreasing glycolysis and leading to the scavenging of reactive oxygen species (ROS), which correlate with a higher resistance to cell death. The decrease in intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic lesions. Given these good prospects of TIGAR for metabolic regulation and p53-response modulation, we analyzed the effects of TIGAR knockdown in U87MG and T98G glioblastoma-derived cell lines. Methods/results: After TIGAR-knockdown in glioblastoma cell lines, different metabolic parameters were assayed, showing an increase in Fru-2,6-P2, lactate and ROS levels, with a concomitant decrease in reduced glutathione (GSH) levels. In addition, cell growth was inhibited without evidence of apoptotic or autophagic cell death. In contrast, a clear senescent phenotype was observed. We also found that TIGAR protein levels were increased shortly after irradiation. In addition, avoiding radiotherapy-triggered TIGAR induction by gene silencing resulted in the loss of capacity of glioblastoma cells to form colonies in culture and the delay of DNA repair mechanisms, based in c-H2AX foci, leading cells to undergo morphological changes compatible with a senescent phenotype. Thus, the results obtained raised the possibility to consider TIGAR as a therapeutic target to increase radiotherapy effects. Conclusion: TIGAR abrogation provides a novel adjunctive therapeutic strategy against glial tumors by increasing radiation-induced cell impairment, thus allowing the use of lower radiotherapeutic doses. 2012-12-05T10:25:19Z 2012-12-05T10:25:19Z 2011-11 2012-12-05T10:25:19Z info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion 0167-8140 https://hdl.handle.net/2445/33005 600411 eng Versió postprint del document publicat a: http://dx.doi.org/10.1016/j.radonc.2011.07.002 Radiotherapy and Oncology, 2011, vol. 101, num. 1, p. 132-139 http://dx.doi.org/10.1016/j.radonc.2011.07.002 (c) Elsevier B.V., 2011 info:eu-repo/semantics/openAccess 8 p. application/pdf Elsevier B.V. Articles publicats en revistes (Infermeria Fonamental i Clínica)