Histone H2AX is a mediator of gastrointestinal stromal tumor cell apoptosis following treatment with imatinib mesylate Journal Article
| Authors: | Liu, Y.; Tseng, M.; Perdreau, S. A.; Rossi, F.; Antonescu, C.; Besmer, P.; Fletcher, J. A.; Duensing, S.; Duensing, A. |
| Article 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 α (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. ©2007 American Association for Cancer Research. |
| Keywords: | controlled study; protein expression; human cell; placebo; nonhuman; antineoplastic agents; ubiquitin; animal cell; mouse; animals; mice; animal tissue; gastrointestinal stromal tumor; imatinib; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; apoptosis; proteasome; enzyme inhibition; animal experiment; animal model; down-regulation; genetic transcription; transcription, genetic; cancer cell culture; cytotoxicity; benzyloxycarbonylvalylalanylaspartyl fluoromethyl ketone; hela cells; pyrimidines; phosphatidylinositol 3 kinase; cancer inhibition; gene expression regulation, neoplastic; ubiquitination; cancer cell; cell aggregation; down regulation; upregulation; piperazines; up-regulation; disease models, animal; drug sensitivity; histone h2ax; histones; chromatin assembly and disassembly |
| Journal Title: | Cancer Research |
| Volume: | 67 |
| Issue: | 6 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2007-03-15 |
| Start Page: | 2685 |
| End Page: | 2692 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-06-3497 |
| PUBMED: | 17363589 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 24" - "Export Date: 17 November 2011" - "CODEN: CNREA" - "Source: Scopus" |
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