Relaxed cell-cycle arrests and propagation of unrepaired chromosomal damage in cancer cell lines with wild-type p53

✍ Scribed by Magali Olivier; Silvia Bautista; Hélène Vallès; Charles Theillet

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 257 KB
• Volume: 23
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/(sici)1098-2744(199809)23:1<1::aid-mc1>3.0.co;2-q

✦ Synopsis

The role of the p53 protein in mediating G 1 and G 2 cell-cycle arrests after genotoxic insult has been clearly and reproducibly established in primary diploid fibroblasts, but data obtained from p53 wild-type (wt) cancer cell lines are inconsistent. Furthermore, a large proportion of human tumors have p53 wt genotypes but present genetic aberrations that may result from defective cell-cycle checkpoints. We therefore 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 that in most cancer cells tested, G 1 arrest was relaxed or absent in comparison with arrest in normal diploid fibroblasts, despite seemingly normal p53 and p21 responses. Two cell lines (MCF7 and HCT116) were synchronized in G 0 /G 1 by leucine starvation and subjected to genotoxic stress to determine more precisely the relative proportion of cells 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-cycle arrests in G 1 and G 2 in response to γ irradiation and bleomycin treatment were transient, as the cells resumed cycling after 48-72 h. The cells resuming proliferation suffered massive apoptosis, but a proportion of the cells were rescued and showed normal doubling times. These cells retained a p53 wt genotype but presented gross chromosomal aberrations in 15-20% of the analyzed metaphases. The aberrations were not clonal. These data show that p53 wt cancer cells have relaxed cell-cycle controls after genotoxic insult and tolerate unrepaired chromosomal damage, despite normal p53 function.