title: Effects of imatinib vary with the types of KIT-mutation in gastrointestinal stromal tumor cell lines.
abstract: Mutations of proto-oncogene c-kit in gastrointestinal stromal tumors (GISTs) are considered to cause a constitutive activation of KIT responsible for their oncogenesis. Imatinib has therapeutic potential for GISTs because of its inhibitory effect on KIT kinase activity. However, no study has been published concerning the effects of imatinib on GIST cells with various types of KIT mutation. To investigate the effects of imatinib on various c-kit mutations found in GISTs, cell proliferation and apoptosis assays were performed in two GIST cell lines with different KIT mutations. One of the cell lines, GIST-T1, revealed a heterozygous deletion of exon 11 in the c-kit, while the other cell line, GIST882, possessed a homozygous missense mutation of exon 13 in the c-kit gene. Imatinib inhibited proliferation and induced apoptosis in both cell lines. Imatinib potently suppressed proliferation of the GIST882 cell line at the concentration of 1.0 microM, whereas it inhibited the GIST-T1 at 0.1 microM. In two types of activating mutant KIT, imatinib could inhibit the constitutive activation of both types of KIT mutant, although the antiproliferative effect on GIST882 was weaker than on GIST-T1. Western blot analysis revealed that apoptosis related proteins were activated or suppressed by imatinib in both cell lines in the respective manner. Our results suggest that the apoptotic signal trans-duction caused by imatinib in GISTs is susceptible to various types of KIT mutation.
authors.affiliation: Department of Gastroenterological Surgery, Okayama University, 2-5-1 Shikata-cho, Okayamashi 700-8558, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Noma
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Naomoto
authors.forename: Mehmet
authors.initials: M
authors.lastname: Gunduz
authors.forename: Junji
authors.initials: J
authors.lastname: Matsuoka
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yamatsuji
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shirakawa
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Nobuhisa
authors.forename: Takaomi
authors.initials: T
authors.lastname: Okawa
authors.forename: Munenori
authors.initials: M
authors.lastname: Takaoka
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Tomono
authors.forename: Ohmori
authors.initials: O
authors.lastname: Hiroyuki
authors.forename: Esra
authors.initials: E
authors.lastname: Gunduz
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C000715470:MAS1 protein, human; D010879:Piperazines; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases