Mutant p53R175H-Associated Protection of Ovarian Cancer Precursor Cells from Cisplatin Requires Expression of SLC6A6 Taurine Transporter

Abstract

Tumor suppressor gene TP53 is ubiquitously mutated in ovarian cancer precursor lesions that undergo pervasive accumulation of DNA damage. Prior literature provides evidence that the expression of mutant p53 protein in epithelial cells is associated with increased survival in response to DNA-damaging treatments.  Hence, identification and understanding of the mechanisms that, in response to DNA damage accumulation, support survival of ovarian cancer precursor cells carrying p53 mutations might provide important information about the evolution of the disease. Here we used a combination of OC precursor cell models, biochemistry, microscopy, and flow cytometry to provide evidence that the taurine transporter, the SLC6A6 molecule, contributes to cell protection from DNA-damaging (cisplatin) treatment. We found that expression of mutant p53^R175H in OC precursor cells, the fallopian tube non-ciliated epithelial (FNE) cells, induced resistance to the DNA-damaging agent cisplatin. Most importantly, shRNA-mediated targeting of SLC6A6 transcript re-sensitized FNE cells expressing mutant p53^R175H to cisplatin treatment. Our studies are consistent with the model that the loss of SLC6A6 alters mechanisms involved in the regulation of cell survival in response to DNA damage.