14-3-3sigma-dependent resistance to cisplatin

Anticancer Res. 2009 Jun;29(6):2009-14.

Abstract

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 14-3-3sigma-knockout (sigma-KO) cells to cisplatin. Moreover, activation of p53, p53-dependent expression of p21 and p21-dependent senescence were observed in sigma-KO, but not parental cells after a treatment with a low cisplatin dose.

Conclusion: A 14-3-3sigma-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins
  • Antineoplastic Agents / pharmacology*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Blotting, Western
  • Cellular Senescence / drug effects
  • Cisplatin / pharmacology*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Cyclin-Dependent Kinase Inhibitor p21 / physiology
  • Drug Resistance, Neoplasm*
  • Exonucleases / genetics
  • Exonucleases / metabolism*
  • Exoribonucleases
  • Flow Cytometry
  • Gene Knockout Techniques
  • Humans
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Tumor Cells, Cultured
  • Tumor Stem Cell Assay
  • Tumor Suppressor Protein p53 / physiology

Substances

  • 14-3-3 Proteins
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Neoplasm Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Exonucleases
  • Exoribonucleases
  • SFN protein, human
  • Cisplatin