Selenoprotein P, as a predictor for evaluating gemcitabine resistance in human pancreatic cancer cells

Int J Cancer. 2004 Nov 1;112(2):184-9. doi: 10.1002/ijc.20304.

Abstract

Gemcitabine is a new standard chemotherapeutic agent used in the treatment of pancreatic cancer, but the mechanisms of gemcitabine sensitivity are still controversial. In our study to determine a mechanism that regulates gemcitabine sensitivity, we carried out molecular analysis on the susceptibility of the pancreatic cancer cells. Using a gemcitabine-sensitive pancreatic cancer cell line KLM1, we established a resistant cell line KLM1-R exhibiting a 20-fold IC50-value (the concentration of gemcitabine causing 50% growth inhibition). Microarray analysis of genes showed specific expression of selenoprotein P, one of the anti-oxidants, in the KLM1-R cell line but not in the KLM1 cell line. Administration of selenoprotein P inhibited the gemcitabine-induced cytotoxicity in the pancreatic cell lines. The levels of intracellular reactive oxygen species (ROS) were increased in the KLM1 cells by gemcitabine, but selenoprotein P suppressed the gemcitabine-induced ROS levels. Furthermore interferon-gamma suppressed the expression of selenoprotein P mRNA and increased intracellular ROS level, leading to the recovery of the gemcitabine sensitivity in KLM1-R. These results suggest a novel mechanism that selenoprotein P reduces the intracellular ROS levels, resulting in the insusceptibility to gemcitabine.

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology*
  • Biomarkers, Tumor / analysis*
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology*
  • Drug Screening Assays, Antitumor
  • Gene Expression Profiling*
  • Humans
  • Interferon-gamma / pharmacology
  • Muscle Proteins
  • Oligonucleotide Array Sequence Analysis
  • Pancreatic Neoplasms / pathology*
  • Protein Biosynthesis
  • Proteins / pharmacology*
  • Reactive Oxygen Species
  • Selenoprotein P
  • Selenoproteins
  • Tumor Cells, Cultured

Substances

  • Antimetabolites, Antineoplastic
  • Biomarkers, Tumor
  • Muscle Proteins
  • Proteins
  • Reactive Oxygen Species
  • Selenoprotein P
  • Selenoproteins
  • Deoxycytidine
  • Interferon-gamma
  • gemcitabine