Selenoprotein P, as a predictor for evaluating gemcitabine resistance in human pancreatic cancer cells.
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.
Maehara
Shin-Ichiro
S
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. shinm@surg2.med.kyushu-u.ac.jp
Tanaka
Shinji
S
Shimada
Mitsuo
M
Shirabe
Ken
K
Saito
Yoshiro
Y
Takahashi
Kazuhiko
K
Maehara
Yoshihiko
Y
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D009124:Muscle Proteins; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000473:pathology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D051149:Selenoprotein P; D051140:Selenoproteins; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D009124:Muscle Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; D051149:Selenoprotein P; D051140:Selenoproteins; D003841:Deoxycytidine; D007371:Interferon-gamma; D000093542:Gemcitabine