Identification and Characterization of a New Platinum-Induced TP53 Mutation in MDAH Ovarian Cancer Cells

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Abstract

Platinum-based chemotherapy is the therapy of choice for epithelial ovarian cancer (EOC). Acquired resistance to platinum (PT) is a frequent event that leads to disease progression and predicts poor prognosis. To understand possible mechanisms underlying acquired PT-resistance, we have recently generated and characterized three PT-resistant isogenic EOC cell lines. Here, we more deeply characterize several PT-resistant clones derived from MDAH-2774 cells. We show that, in these cells, the increased PT resistance was accompanied by the presence of a subpopulation of multinucleated giant cells. This phenotype was likely due to an altered progression through the M phase of the cell cycle and accompanied by the deregulated expression of genes involved in M phase progression known to be target of mutant TP53. Interestingly, we found that PT-resistant MDAH cells acquired in the TP53 gene a novel secondary mutation (i.e., S185G) that accompanied the R273H typical of MDAH cells. The double p53S185G/R273H mutant increases the resistance to PT in a TP53 null EOC cellular model. Overall, we show how the selective pressure of PT is able to induce additional mutation in an already mutant TP53 gene in EOC and how this event could contribute to the acquisition of novel cellular phenotypes.
Original languageEnglish
Number of pages18
JournalCells
Volume9
Issue number1
DOIs
Publication statusPublished - 2020

Keywords

  • aberrant mitosis
  • epithelial ovarian cancer
  • multinucleated giant cells
  • platinum resistant cells
  • TP53 secondary mutations
  • antineoplastic agent
  • platinum
  • protein p53
  • TP53 protein, human
  • cell cycle
  • cell survival
  • drug effect
  • drug resistance
  • female
  • genetics
  • human
  • metabolism
  • mitosis
  • mutation
  • ovary
  • ovary tumor
  • pathology
  • tumor cell line
  • Antineoplastic Agents
  • Carcinoma, Ovarian Epithelial
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Survival
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Mitosis
  • Mutation
  • Ovarian Neoplasms
  • Ovary
  • Platinum
  • Tumor Suppressor Protein p53

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