All-trans retinoic acid inhibits KIT activity and induces apoptosis in gastrointestinal stromal tumor GIST-T1 cell line by affecting on the expression of survivin and Bax protein

• Published in: Journal of experimental & clinical cancer research Vol. 29; no. 1; p. 165
• Main Authors: Hoang, Thanh Chi, Bui, Thi Kim Ly, Taguchi, Takahiro, Watanabe, Toshiki, Sato, Yuko
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 16.12.2010; BioMed Central; BMC
• Subjects: Acids; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; bcl-2-Associated X Protein - biosynthesis; Blotting, Western; Cell Line, Tumor; Cell lines; Cell Proliferation - drug effects; Diagnosis; DNA Fragmentation; Dosage and administration; Drug therapy; Gastrointestinal Stromal Tumors - drug therapy; Gastrointestinal Stromal Tumors - metabolism; Gastrointestinal tumors; Gene expression; Gene Expression - drug effects; Genetic aspects; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins - biosynthesis; Mutation; Physiological aspects; Proteins; Proto-Oncogene Proteins c-kit - drug effects; Proto-Oncogene Proteins c-kit - metabolism; Studies; Tretinoin; Tretinoin - pharmacology; Vitamin A; Japan
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/1756-9966-29-165

Imatinib, a selective tyrosine kinase inhibitor, has been used as a standard first-line therapy for irresectable and metastasized gastrointestinal stromal tumor (GIST) patients. Unfortunately, most patients responding to imatinib will eventually exhibit imatinib-resistance, the cause of which is not fully understood. The serious clinical problem of imatinib-resistance demands alternative therapeutic strategy. This study was conducted to investigate the effect of all-trans retinoic acid (ATRA) on GIST cell lines. Cell proliferation was determined by trypan blue dye exclusion test. Western blot analysis was performed to test the expression of activated KIT, its downstream proteins, and apoptosis associated proteins. The cytotoxic interactions of imatinib with ATRA were evaluated using the isobologram of Steel and Peckham. In this work, for the first time we have demonstrated that ATRA affected on cell proliferation of GIST-T1 and GIST-882 cell line through inhibition of cell growth in a dose dependent manner and induced apoptosis. High dose of ATRA induced morphologic change in GIST-T1 cells, rounded-up cells, and activated the caspase-3 protein. In further examination, we found that the ATRA-induced apoptosis in GIST-T1 cells was accompanied by the down-regulated expression of survivin and up-regulated expression of Bax protein. Moreover, ATRA suppressed the activity of KIT protein in GIST-T1 cells and its downstream signal, AKT activity, but not MAPK activity. We also have demonstrated that combination of ATRA with imatinib showed additive effect by isobologram, suggesting that the combination of ATRA and imatinib may be a novel potential therapeutic option for GIST treatment. Furthermore, the scracht assay result suggested that ATRA was a potential reagent to prevent the invasion or metastasis of GIST cells.