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.
Highlights
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 a (PDGFRA) tyrosine kinases [1,2,3]
These results show that the apoptotic response of GIST cells to imatinib is time dependent, and that a major increase of cell death occurs with a considerable delay after onset of treatment
An in vitro ubiquitination assay using recombinant human H2AX as substrate showed that GIST882 cell lysate promotes the polyubiquitination of human recombinant H2AX (Fig. 2F). These results suggest that oncogenic KIT decreases H2AX levels through stimulation of its ubiquitin-mediated degradation and is in line with findings that H2AX mRNA levels were not up-regulated in a GIST mouse model after imatinib treatment
Summary
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 a (PDGFRA) tyrosine kinases [1,2,3]. 4), 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 [5], but which potently inhibits the PDGFR family members (PDGFRA, PDGFRB) and KIT [6]. The mechanistic events by which KIT/ PDGFRA kinase inhibition leads to clinical responses in GIST patients are not known in detail. By identifying the biochemical mediators of imatinib-induced GIST cell death, it might be possible to develop innovative strategies to induce more complete responses, overcome imatinib resistance, and to enable more effective disease control with an aim toward cure. A better understanding of the mode of action of imatinib may help to identify other tumor types that can be treated with small-molecule protein kinase antagonists
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