STI571 (Glivec) inhibits the interaction between c-KIT and heat shock protein 90 of the gastrointestinal stromal tumor cell line, GIST-T1.

Abstract

The gastrointestinal stromal tumor cell line, GIST-T1, has a heterogenic 57-base pair deletion in exon 11 of the c-kit mutation, and the c-KIT protein in the GIST-T1 cells constitutively activated. We report that STI571 (Glivec; Novartis, Basel, Switzerland), a specific inhibitor of c-KIT, inhibits the clustering of c-KIT at the cell membrane of the GIST-T1 cells. Furthermore, STI571 prevents the interaction between c-KIT and the molecular chaperone, heat shock protein 90 (Hsp90). Geldanamycin, an inhibitor of Hsp90, also prevents interaction between c-KIT and Hsp90, and inhibits tyrosine phosphorylation of c-KIT. Our results indicate that c-KIT molecules are assembled on the cell surface of the GIST-T1 cells, and that the interaction between c-KIT and Hsp90 plays an important role in c-KIT activation.

• Authors: Hajime Nakatani, Michiya Kobayashi, Toufeng Jin, Takahiro Taguchi, Takeki Sugimoto, Takumi Nakano, Shinichi Hamada, Keijiro Araki
• Journal: Cancer science (Cancer Sci) Vol. 96 Issue 2 Pg. 116-9 (Feb 2005) ISSN: 1347-9032 [Print] England
• PMID: 15723656 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Piperazines
• Pyrimidines
• Quinones
• Imatinib Mesylate
• Proto-Oncogene Proteins c-kit
• geldanamycin

Topics

• Benzamides
• Benzoquinones
• Cell Line, Tumor
• Cell Membrane (metabolism)
• Cell Survival (drug effects)
• Drug Interactions
• Gastrointestinal Stromal Tumors
• HSP90 Heat-Shock Proteins (metabolism)
• Humans
• Imatinib Mesylate
• Lactams, Macrocyclic
• Phosphorylation
• Piperazines (pharmacology)
• Proto-Oncogene Proteins c-kit (metabolism)
• Pyrimidines (pharmacology)
• Quinones (pharmacology)