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J.Health Sci., 52(2), 110-117, 2006
Thapsigargin Enhances Cell Death in the Gastrointestinal Stromal Tumor Cell Line, GIST-T1, by Treatment with Imatinib (Glivec)
Toufeng Jin,a, f Hajime Nakatani,*, b Takahiro Taguchi,c Hiroshi Sonobe,d Norihito Morimoto,e Takeki Sugimoto,b Toyokazu Akimori,b Takumi Nakano,b Tsutomu Namikawa,b Takehiro Okabayashi,b Michiya Kobayashi,b and Keijiro Arakib
aDoctoral Course, Medical Graduate School of Kochi University, bDepartment of Tumor Surgery, Kochi Medical School, Kochi University, Okou, Nankoku, Kochi 783-8505, Japan, cDepartment of Human and Medical Science, Graduate School of Kuroshio Science, Kochi University, Monobe, Nankoku, Kochi 783-8503, Japan, dDepartment of Laboratory Medicine and Pathology, National Hospital Organization, Fukuyama Medical Center, Okinogami, Fukuyama, Hiroshima 720-0825, Japan, eDepartment of Clinical Laboratory Medicine, Kochi Medical School, Kochi University, Okou, Nankoku, Kochi 783-8505, Japan, and fDepartment of General Surgery, College of Medical, Yanbian University, 119 Juzijie, Yanjishi, Jilin Province, China
Imatinib is a specific inhibitor of c-KIT that has recently been approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumor (GIST). Thapsigargin is an inhibitor of calcium transport to the endoplasmic reticulum (ER) and can inhibit protein maturation. In this study, we evaluated the synergistic cytotoxic effect of thapsigargin and imatinib on the GIST cell line, GIST-T1. Cell viability and cell death were determined by 3,-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. In addition, the amount and activation of c-KIT on the cell surface were measured by flow cytometry and western blot analysis, respectively. Thapsigargin alone (for 5 hr incubation) was shown to decrease the amount of c-KIT on the GIST-T1 cell surface and to slightly inhibit the associated tyrosine kinase activity. Interestingly, thapsigargin significantly enhanced the cell death induced by imatinib compared with the effect of imatinib alone. The results further suggested that thapsigargin induced the increased cell death in GIST-T1 cells co-treated with imatinib, at least in part, via disrupting the translocation of c-KIT to the cell surface, and decreasing the activated c-KIT molecules.
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