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Selenoprotein P, as a predictor for evaluating gemcitabine resistance in human pancreatic cancer cells
Author(s) -
Maehara Shinichiro,
Tanaka Shinji,
Shimada Mitsuo,
Shirabe Ken,
Saito Yoshiro,
Takahashi Kazuhiko,
Maehara Yoshihiko
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20304
Subject(s) - gemcitabine , pancreatic cancer , selenoprotein , intracellular , cancer research , cell culture , chemistry , selenoprotein p , biology , cancer , medicine , microbiology and biotechnology , biochemistry , enzyme , glutathione , glutathione peroxidase , genetics
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 IC 50 ‐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‐γ 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. © 2004 Wiley‐Liss, Inc.