Jacqueline Kessler1, Antje Güttler2, Henri Wichmann3, Swetlana Rot4, Matthias Kappler5, Matthias Bache6, Dirk Vordermark7. 1. Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Germany. Electronic address: jacqueline.kessler@uk-halle.de. 2. Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Germany. Electronic address: antje.hahnel@uk-halle.de. 3. Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Germany. Electronic address: henri.wichmann@uk-halle.de. 4. Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, Germany. Electronic address: swetlana.rot@uk-halle.de. 5. Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, Germany. Electronic address: matthias.kappler@uk-halle.de. 6. Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Germany. Electronic address: matthias.bache@uk-halle.de. 7. Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Germany. Electronic address: dirk.vordermark@uk-halle.de.
Abstract
BACKGROUND AND PURPOSE: In malignant glioma the presence of the IDH1 mutation (IDH1(R132H)) is associated with better clinical outcome. However, it is unclear whether IDH1 mutation is associated with a less aggressive phenotype or directly linked to increased sensitivity to radiotherapy. MATERIAL AND METHODS: We determined the influence of IDH1(R132H) mutant protein on proliferation and growth in 3D culture, migration, cell survival and radiosensitivity in vitro under normoxia (21% O2) and hypoxia (<1% O2) in a panel of human malignant glioma cell lines (U-251MG, U-343MG, LN-229) with stable overexpression of wild-type (IDH1(wt)) and mutated IDH1 (IDH1(R132H)). RESULTS: Overexpression of IDH1(R132H) in glioma cells resulted in slightly decreased cell proliferation, considerably reduced cell migration and caused differences in growth properties in 3D spheroid cultures. Furthermore, IDH1(R132H)-positive cells consistently demonstrated an increased radiosensitivity in human malignant glioma cells U-251MG (DMF10: 1.52, p<0.01 and 1.42, p<0.01), U-343MG (DMF10: 1.78, p<0.01 and 1.75, p<0.01) and LN-229 (DMF10: 1.41, p<0.05 and 1.68, p<0.01) under normoxia and hypoxia, respectively. CONCLUSION: Our data indicate that IDH1(R132H) mutation causes both a less aggressive biological behavior and direct radiosensitization of human malignant glioma cells. Targeting IDH1 appears to be an attractive approach in combination with radiotherapy.
BACKGROUND AND PURPOSE: In malignant glioma the presence of the IDH1 mutation (IDH1(R132H)) is associated with better clinical outcome. However, it is unclear whether IDH1 mutation is associated with a less aggressive phenotype or directly linked to increased sensitivity to radiotherapy. MATERIAL AND METHODS: We determined the influence of IDH1(R132H) mutant protein on proliferation and growth in 3D culture, migration, cell survival and radiosensitivity in vitro under normoxia (21% O2) and hypoxia (<1% O2) in a panel of humanmalignant glioma cell lines (U-251MG, U-343MG, LN-229) with stable overexpression of wild-type (IDH1(wt)) and mutated IDH1 (IDH1(R132H)). RESULTS: Overexpression of IDH1(R132H) in glioma cells resulted in slightly decreased cell proliferation, considerably reduced cell migration and caused differences in growth properties in 3D spheroid cultures. Furthermore, IDH1(R132H)-positive cells consistently demonstrated an increased radiosensitivity in humanmalignant glioma cells U-251MG (DMF10: 1.52, p<0.01 and 1.42, p<0.01), U-343MG (DMF10: 1.78, p<0.01 and 1.75, p<0.01) and LN-229 (DMF10: 1.41, p<0.05 and 1.68, p<0.01) under normoxia and hypoxia, respectively. CONCLUSION: Our data indicate that IDH1(R132H) mutation causes both a less aggressive biological behavior and direct radiosensitization of humanmalignant glioma cells. Targeting IDH1 appears to be an attractive approach in combination with radiotherapy.
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