Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species.
Glioblastoma multiforme (GBM) is among the most lethal of human malignancies. Most GBM tumors are refractory to cytotoxic therapies. Glioma stem cells (GSCs) significantly contribute to GBM progression and post-treatment tumor relapse, therefore serving as a key therapeutic target; however, GSCs are resistant to conventional radiation therapy. Proton therapy is one of the newer cancer treatment modalities and its effects on GSCs function remain unclear. Here, by utilizing patient-derived GSCs, we show that proton radiation generates greater cytotoxicity in GSCs than x-ray photon radiation. Compared with photon radiation, proton beam irradiation induces more single and double strand DNA breaks, less H2AX phosphorylation, increased Chk2 phosphorylation, and reduced cell cycle recovery from G2 arrest, leading to caspase-3 activation, PARP cleavage, and cell apoptosis. Furthermore, proton radiation generates a large quantity of reactive oxygen species (ROS), which is required for DNA damage, cell cycle redistribution, apoptosis, and cytotoxicity. Together, these findings indicate that proton radiation has a higher efficacy in treating GSCs than photon radiation. Our data reveal a ROS-dependent mechanism by which proton radiation induces DNA damage and cell apoptosis in GSCs. Thus, proton therapy may be more efficient than conventional x-ray photon therapy for eliminating GSCs in GBM patients.
Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA 19104.
R
R
Alan Mitteer
Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA 19104.
Yanling
Y
Wang
Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA 19104.|Lehigh University, Bethlehem, Pennsylvania, USA 18015.
Jennifer
J
Shah
Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA 19104.|Drexel University, Philadelphia, Pennsylvania, USA 19104.
Sherika
S
Gordon
Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA 19104.|Department of Physics &Astronomy, University of Pennsylvania, Philadelphia, Pennsylvania, USA 19104.
Marcus
M
Fager
Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA 19104.|Drexel University, Philadelphia, Pennsylvania, USA 19104.
Param-Puneet
PP
Butter
Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA 19104.
Hyun
H
Jun Kim
Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA 19104.
Consuelo
C
Guardiola-Salmeron
Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA 19104.
Alejandro
A
Carabe-Fernandez
Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA 19104.
Yi
Y
Fan
D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects*; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair / Q000528:radiation effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000528:radiation effects; D005910:Glioma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000528:radiation effects*; D010766:Phosphorylation; D017785:Photons / Q000009:adverse effects; D011494:Protein Kinases / Q000378:metabolism; D011522:Protons / Q000009:adverse effects*; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism*
D011522:Protons; D017382:Reactive Oxygen Species; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; D000071877:Checkpoint Kinase 1