14-3-3σ-Dependent Resistance to Cisplatin

Background: A major factor that impedes the clinical success of cisplatin-based chemotherapy for cancer is cisplatin resistance by cancer cells. Materials and Methods: The sensitivity of parental HCT116 human colon cancer cell line and its isogenic gene-knockout sub-lines to cisplatin was determined by clonogenicity assay; furthermore, p53 activation, p21 expression, cell cycle arrest and senescence in these cells after cisplatin treatment were investigated. Results: Parental cells were six times more resistant than 14-3-3σ-knockout (σ-KO) cells to cisplatin. Moreover, activation of p53, p53-dependent expression of p21 and p21-dependent senescence were observed in σ-KO, but not parental cells after a treatment with a low cisplatin dose. Conclusion: A 14-3-3σ-dependent mechanism inhibits p53 activation in parental cells treated with a low cisplatin dose, thereby blocking p21 expression that is essential for senescence and consequently conferring to the parental cells a significant degree of resistance to cisplatin. Cisplatin is an important anticancer drug and its anticancer activity is due to its ability to react, after it is activated inside the cell, with DNA to form covalent platinum (Pt)-DNA adducts (Pt adducts), which, if not repaired, trigger a DNA damage response that results in cell cycle arrest and/or