Proapoptotic activity of bortezomib in gastrointestinal stromal tumor cells.

Abstract

Gastrointestinal stromal tumors (GIST) are caused by activating mutations in the KIT or PDGFRA receptor tyrosine kinase genes. Although >85% of GIST patients treated with the small-molecule inhibitor imatinib mesylate (Gleevec) achieve disease stabilization, complete remissions are rare and a substantial proportion of patients develop resistance to imatinib over time. Upregulation of soluble, non-chromatin-bound histone H2AX has an important role in imatinib-induced apoptosis of GIST cells. Additionally, H2AX levels in untreated GIST are maintained at low levels by a pathway that involves KIT, phosphoinositide 3-kinase, and the ubiquitin-proteasome system. In this study, we asked whether bortezomib-mediated inhibition of the ubiquitin-proteasome machinery could lead to upregulation of histone H2AX and GIST cell death. We show that bortezomib rapidly triggers apoptosis in GIST cells through a combination of mechanisms involving H2AX upregulation and loss of KIT protein expression. Downregulation of KIT transcription was an underlying mechanism for bortezomib-mediated inhibition of KIT expression. In contrast, the nuclear factor-kappaB signaling pathway did not seem to play a major role in bortezomib-induced GIST cell death. Significantly, we found that bortezomib would induce apoptosis in two imatinib-resistant GIST cell lines as well as a short-term culture established from a primary imatinib-resistant GIST. Collectively, our results provide a rationale to test the efficacy of bortezomib in GIST patients with imatinib-sensitive or -resistant tumors.

DOI: 10.1158/0008-5472.CAN-09-1449

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@article{Bauer2010ProapoptoticAO, title={Proapoptotic activity of bortezomib in gastrointestinal stromal tumor cells.}, author={Sebastian Bauer and Joshua A Parry and Thomas M{\"{u}hlenberg and Matthew F Brown and Danushka Seneviratne and Payel Chatterjee and Anna Chin and Brian P Rubin and Shih-Fan Kuan and Jonathan A Fletcher and Stefan Duensing and Anette Duensing}, journal={Cancer research}, year={2010}, volume={70 1}, pages={150-9} }