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 unc ertain. We have reported previously that ionizing radiation induces centros ome overduplication in human tumor cells. The present study was designed to elucidate a possible link between centrosome dysregulation and radiation-i nduced cell death. Exposure to 10 Gy gamma -radiation resulted in a substan tial increase in cells containing an abnormally high number of centrosomes in a variety of cell lines derived from different types of human solid tumo rs. These aberrant centrosomes contribute to the assembly of multipolar spi ndles, thereby causing an unbalanced division of chromosomes and mitotic ce ll death characterized by the appearance of multi- or micronucleated cells. An extensive analysis of a panel of 10 tumor cell lines revealed a positiv e correlation between the fraction of cells with multiple centrosomes and t he fraction with these nuclear abnormalities after irradiation. When the ce ntrosome overduplication was blocked by enforced expression of p21(Waf1/Cip 1), 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 exposu re to ionizing radiation.