IDH1(R132H) mutation causes a less aggressive phenotype and radiosensitizes human malignant glioma cells independent of the oxygenation status.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Germany. Electronic address: jacqueline.kessler@uk-halle.de.
Jacqueline
J
Kessler
Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Germany. Electronic address: antje.hahnel@uk-halle.de.
Antje
A
Güttler
Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Germany. Electronic address: henri.wichmann@uk-halle.de.
Henri
H
Wichmann
Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, Germany. Electronic address: swetlana.rot@uk-halle.de.
Swetlana
S
Rot
Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, Germany. Electronic address: matthias.kappler@uk-halle.de.
Matthias
M
Kappler
Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Germany. Electronic address: matthias.bache@uk-halle.de.
Matthias
M
Bache
Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Germany. Electronic address: dirk.vordermark@uk-halle.de.
Dirk
D
Vordermark
D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000532:radiotherapy*; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000503:physiopathology; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D011836:Radiation Tolerance / Q000235:genetics* / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
D011838:Radiation-Sensitizing Agents; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
Glioma; Hypoxia; IDH1; IDH1(R132H); Isocitrate dehydrogenase 1; Radiation