A possible role for centrosome overduplication in radiation-induced cell death.
Radiotherapy plays a key role in the treatment of many tumors; however, the precise mechanisms responsible for radiation-induced cell death remain uncertain. We have reported previously that ionizing radiation induces centrosome overduplication in human tumor cells. The present study was designed to elucidate a possible link between centrosome dysregulation and radiation-induced cell death. Exposure to 10 Gy gamma-radiation resulted in a substantial increase in cells containing an abnormally high number of centrosomes in a variety of cell lines derived from different types of human solid tumors. These aberrant centrosomes contribute to the assembly of multipolar spindles, thereby causing an unbalanced division of chromosomes and mitotic cell death characterized by the appearance of multi- or micronucleated cells. An extensive analysis of a panel of 10 tumor cell lines revealed a positive correlation between the fraction of cells with multiple centrosomes and the fraction with these nuclear abnormalities after irradiation. When the centrosome overduplication was blocked by enforced expression of p21Waf1/Cip1, the radiation-induced lethality was drastically rescued. Taken together, these results indicate that centrosome overduplication may be a critical event leading to mitotic failure and subsequent cell death following exposure to ionizing radiation.
Sato
N
N
Department of Surgery and Oncology, Gradulate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Mizumoto
K
K
Nakamura
M
M
Ueno
H
H
Minamishima
Y A
YA
Farber
J L
JL
Tanaka
M
M
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000328:Adult; D017209:Apoptosis / Q000528:radiation effects; D002453:Cell Cycle / Q000528:radiation effects; D016923:Cell Death / Q000528:radiation effects*; D002467:Cell Nucleus / Q000473:pathology / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D018385:Centrosome / Q000473:pathology* / Q000528:radiation effects*; D020090:Chromosome Segregation / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D005720:Gamma Rays; D006801:Humans; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000528:radiation effects; D010641:Phenotype; D008941:Spindle Apparatus / Q000473:pathology / Q000528:radiation effects; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins