Proapoptotic activity of bortezomib in gastrointestinal stromal tumor cells.
Proapoptotic activity of bortezomib in gastrointestinal stromal tumor cells.
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DOI：
10.1158/0008-5472.can-09-1449
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发表时间：
2010-01-01
期刊：
影响因子：
11.2
通讯作者：
Duensing A
中科院分区：
文献类型：
--
作者：
Bauer S;Parry JA;Mühlenberg T;Brown MF;Seneviratne D;Chatterjee P;Chin A;Rubin BP;Kuan SF;Fletcher JA;Duensing S;Duensing A
胃肠道间质瘤 (GIST) 是由 KIT 或 PDGFRA 受体酪氨酸激酶基因的激活突变引起的。尽管接受小分子抑制剂甲磺酸伊马替尼 (Gleevec®) 治疗的 GIST 患者中，超过 85% 的患者病情稳定，但完全缓解的情况很少见，而且随着时间的推移，相当一部分患者会对伊马替尼产生耐药性。我们之前报道过，可溶性非染色质结合组蛋白 H2AX 的上调在伊马替尼诱导的 GIST 细胞凋亡中具有重要作用，并且在未经治疗的 GIST 中，H2AX 水平通过涉及 KIT、PI3K 和泛素蛋白酶体系统的途径维持在较低水平。在这里，我们询问硼替佐米介导的泛素蛋白酶体机制的抑制是否会导致组蛋白 H2AX 上调和 GIST 细胞死亡。我们发现，硼替佐米通过 H2AX 上调和 KIT 蛋白表达缺失的联合机制快速引发 GIST 细胞凋亡。我们证明 KIT 转录下调是硼替佐米介导的 KIT 表达抑制的潜在机制。核因子-κ-B (NF-κB) 信号通路的调节似乎在硼替佐米诱导的 GIST 细胞死亡中并未发挥主要作用。重要的是，硼替佐米诱导了两种伊马替尼耐药 GIST 细胞系以及由伊马替尼耐药 GIST 建立的短期培养物细胞凋亡。总的来说，我们的结果表明，使用硼替佐米抑制蛋白酶体可以在体外有效杀死伊马替尼敏感和伊马替尼耐药的 GIST 细胞，并为测试硼替佐米在 GIST 患者中的疗效提供依据。
Gastrointestinal stromal tumors (GISTs) are caused by activating mutations in the KIT or PDGFRA receptor tyrosine kinase genes. Although more than 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. We previously reported that upregulation of soluble, non chromatin-bound histone H2AX has an important role in imatinib-induced GIST cell apoptosis and that H2AX levels, in untreated GIST, are maintained at low levels by a pathway that involves KIT, PI3K, and the ubiquitin-proteasome system. Here, 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. We demonstrate downregulation of KIT transcription as an underlying mechanism for bortezomib-mediated inhibition of KIT expression. Modulation of the nuclear factor-kappa-B (NF-κB) signaling pathway did not appear to play a major role in bortezomib-induced GIST cell death. Importantly, bortezomib induced apoptosis in two imatinib-resistant GIST cell lines as well as a short-term culture established from an imatinib-resistant GIST. Collectively, our results show that inhibition of the proteasome using bortezomib can effectively kill imatinib-sensitive and imatinib-resistant GIST cells in vitro and provide a rationale to test the efficacy of bortezomib in GIST patients.