Molecular response of human glioblastoma multiforme cells to ionizing radiation: cell cycle arrest, modulation of the expression of cyclin-dependent kinase inhibitors, and autophagy.
OBJECTIVE
Ionizing radiation is the gold-standard adjuvant treatment for glioblastoma multiforme (GBM), the most aggressive primary brain tumor. The mechanisms underlying neoplastic glial cell growth inhibition after administration of ionizing radiation, however, remain largely unknown. In this report, the authors characterize the response of GBM cells to ionizing radiation and elucidate factors that correlate with the radiosensitivity of these tumors.


METHODS
Six human GBM cell lines were subjected to increasing doses of radiation. Each demonstrated a dose-dependent suppression of cell proliferation. In the most radiosensitive cell line, the authors demonstrated a transient increase in the expression of the cyclin-dependent kinase inhibitors (CDKIs) p21 and p27, which corresponded with a G1 cell-cycle arrest. In contrast, the most radioresistant cell line demonstrated a decrease in p21 and p27 expression levels, which correlated with a failure to arrest. Apoptosis did not occur in any cell line following irradiation. Instead, autophagic cell changes were observed following administration of radiation, regardless of the relative radiosensitivity of the cell line.


CONCLUSIONS
These findings elucidate some of the molecular responses of GBMs to irradiation and suggest novel targets for future therapy.
Yao
Kevin C
KC
Department of Neurosurgery, Mount Sinai School of Medicine, New York, New York, USA.
Komata
Tadashi
T
Kondo
Yasuko
Y
Kanzawa
Takao
T
Kondo
Seiji
S
Germano
Isabelle M
IM
D001343:Autophagy / Q000235:genetics* / Q000528:radiation effects*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy*; D018797:Cell Cycle Proteins / Q000032:analysis / Q000528:radiation effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000032:analysis / Q000528:radiation effects*; D004791:Enzyme Inhibitors / Q000032:analysis / Q000528:radiation effects*; D016193:G1 Phase / Q000235:genetics* / Q000528:radiation effects*; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy*; D006801:Humans; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D015388:Organelles / Q000235:genetics / Q000528:radiation effects; D011836:Radiation Tolerance / Q000235:genetics / Q000528:radiation effects; D011839:Radiation, Ionizing; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000473:pathology / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000528:radiation effects*
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27