RELAXED CELL-CYCLE ARRESTS AND PROPAGATION OF UNREPAIRED CHROMOSOMAL DAMAGE IN CANCER CELL-LINES WITH WILD-TYPE P53

The role of the p53 protein in mediating G(1) and G(2) cell-cycle arre sts after genotoxic insult has been clearly and reproducibly establish ed in primary diploid fibroblasts, but data obtained from p53 wild-typ e (wt) cancer cell lines are inconsistent. Furthermore, a large propor tion of human tumors have p53 wt genotypes but present genetic aberrat ions that may result from defective cell-cycle checkpoints. We therefo re investigated the integrity of G(1)/S and G(2)/M cell-cycle arrests in p53 wt: cancer cell lines. In the study presented here, we showed t hat in most cancer cells tested, G(1) arrest was relaxed or absent in comparison with arrest in normal diploid fibroblasts, despite seemingl y normal p53 and p21 responses. Two cell lines (MCF7 and HCT11G) were synchronized in G(0)G(1) by leucine starvation and subjected to genoto xic stress to determine more precisely the relative proportion of cell s arresting in G(1) and G(2). Whereas the MCF7 cells showed consistent G(1) arrest, the HCT116 cells showed none at all. Furthermore, cell-c ycle arrests in G(1) and G(2) in response to gamma irradiation and ble omycin treatment were transient, as the cells resumed cycling after 48 -72 h. The cells resuming proliferation suffered massive apoptosis, bu t a proportion of the cells were rescued and showed normal doubling ti mes. These cells retained a p53 wt genotype but presented gross chromo somal aberrations in 15-20% of the analyzed metaphases. The aberration s were not clonal. These data show that p53 wt cancer cells have relax ed cell-cycle controls after genotoxic insult and tolerate unrepaired chromosomal damage, despite normal p53 function. (C) 1998 Wiley-Liss, Inc.