p53 mediates hydroxyurea resistance in aneuploid cells of colon cancer

Aneuploidy refers to aberrancies in cellular chromosome count, which is prevalent in most human cancers. Chemotherapy is an effective cancer treatment; however, the development of drug resistance is a major concern of conventional chemotherapy. The chemotherapy agent hydroxyurea (HU) targets proliferating cells and has long been applied to treat various human cancers. It remains elusive whether aneuploidy affects the drug sensitivity of hydroxyurea. By generating an inducible aneuploidy model, we found that aneuploid colon cancer cells were resistant to HU treatment compared to euploid controls. Surprisingly, further analyses showed that the HU resistance was dependent on the expression of wild type p53. Activation of the p53 pathway in aneuploidy cells reduced cell proliferation but generated resistance of tumor cells to HU treatment. HU resistance was abrogated in aneuploid cells if p53 was absent but re-gained when inducing proliferation repression in cells by serum deprivation. Our results demonstrate that the HU resistance developed in aneuploid colon cancer cells is mediated by wild type p53 and indicates the prognostic value of combining karyotypic and p53 status in clinical cancer treatment.