title: Histone H2AX is a mediator of gastrointestinal stromal tumor cell apoptosis following treatment with imatinib mesylate.
abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and are caused by activating mutations of the KIT or platelet-derived growth factor receptor alpha (PDGFRA) tyrosine kinases. GISTs can be successfully treated with imatinib mesylate, a selective small-molecule protein kinase inhibitor that was first clinically approved to target the oncogenic BCR-ABL fusion protein kinase in chronic myelogenous leukemia, but which also potently inhibits KIT and PDGFR family members. The mechanistic events by which KIT/PDGFRA kinase inhibition leads to clinical responses in GIST patients are not known in detail. We report here that imatinib triggers GIST cell apoptosis in part through the up-regulation of soluble histone H2AX, a core histone H2A variant. We found that untreated GIST cells down-regulate H2AX in a pathway that involves KIT, phosphoinositide-3-kinase, and the ubiquitin/proteasome machinery, and that the imatinib-mediated H2AX up-regulation correlates with imatinib sensitivity. Depletion of H2AX attenuated the apoptotic response of GIST cells to imatinib. Soluble H2AX was found to sensitize GIST cells to apoptosis by aberrant chromatin aggregation and a transcriptional block. Our results underscore the importance of H2AX as a human tumor suppressor protein, provide mechanistic insights into imatinib-induced tumor cell apoptosis and establish H2AX as a novel target in cancer therapy.
authors.affiliation: Molecular Virology Program, University of Pittsburgh Cancer Institute, Pennsylvania 15213, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Michelle
authors.initials: M
authors.lastname: Tseng
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Perdreau
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Rossi
authors.forename: Cristina
authors.initials: C
authors.lastname: Antonescu
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Stefan
authors.initials: S
authors.lastname: Duensing
authors.forename: Anette
authors.initials: A
authors.lastname: Duensing
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides; D004195:Disease Models, Animal; D015536:Down-Regulation; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006657:Histones / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C468783:H2AX protein, human; D006657:Histones; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit