Polyploidization increases the sensitivity to DNA-damaging agents in mammalian cells

Abstract

Polyploidization occurs during normal development. In the last decades, numerous evidences showed that polyploidization also involves in either an early step or a critical promoting factor in tumorigenesis. In this study, I investigated whether ploidy influences the response of cancer cells to genotoxic agents. Using a novel polyploid system, Hep3B-T cells, generated by prolonged nocodazole treatment of Hep3B cells followed by mitotic slippage and re-replication of the DNA, the genotoxicity of the new tetraploid cells was compared with its diploid counterpart. I found that tetraploidization increased the cell volume without affecting the cell cycle distribution and doubling time. In spite of the centrosome overduplication due to polyploidization, the majority of Hep3B-T cells underwent bipolar mitosis. Polyploidization sensitized cells to genotoxic agents inflicted by ionizing radiation and topoisomerase inhibitors without affecting the sensitivity to spindle inhibitors. Accordingly, I found that more gamma-H2AX foci, a molecular marker present on sites of DNA damage, were induced by radiation in Hep3B-T cells than in Hep3B cells. Furthermore, similar increase in radiosensitivity occurred in primary tetraploid fibroblasts in comparison with normal diploid fibroblasts. These results raise an implication for chemotherapy of which some cancer cells may be sensitized to genotoxic agents by a preceding step that induces polyploidization