Molecular chaperone gp96 is a novel therapeutic target of multiple myeloma.
Molecular chaperone gp96 is a novel therapeutic target of multiple myeloma.
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DOI：
10.1158/1078-0432.ccr-13-2083
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发表时间：
2013-11-15
期刊：
影响因子：
--
通讯作者：
Liu B
中科院分区：
文献类型：
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作者：
Hua Y;White-Gilbertson S;Kellner J;Rachidi S;Usmani SZ;Chiosis G;Depinho R;Li Z;Liu B
gp96 (grp94) 是 ER 中介导未折叠蛋白反应 (UPR) 的关键下游伴侣，多发性骨髓瘤 (MM) 的发病机制与 UPR 失调密切相关。在本研究中，我们旨在确定 gp96 在体内和体外 MM 发生和进展中的作用。我们构建了 B 细胞室中 XBP1 过度表达和 gp96 同时条件性缺失的小鼠模型，以鉴定 gp96 在体内 MM 发展中的作用。使用shRNA系统，我们沉默了多个人MM细胞中的gp96，并通过细胞增殖、细胞周期分析、凋亡测定、免疫组织化学和人骨髓瘤异种移植模型检查了gp96敲低对MM细胞的影响。通过细胞凋亡实验和MTT实验评价gp96选择性抑制剂WS13的抗癌活性。 XBP1s-Tg 小鼠中 gp96 的基因缺失可减轻多发性骨髓瘤。 gp96 的沉默通过抑制 Wnt-LRP-survivin 途径导致人类 MM 细胞生长严重受损。我们还证实，在小鼠异种移植模型中，gp96 的敲低可降低人类 MM 的生长。靶向 gp96 抑制剂诱导细胞凋亡并阻断 MM 细胞生长，但不诱导前 B 白血病细胞凋亡。我们已经证明骨髓瘤的生长在遗传和药理学上都依赖于 gp96。 gp96 对于 MM 细胞增殖和存活至关重要，表明 gp96 是多发性骨髓瘤的新治疗靶点。
gp96 (grp94) is a key downstream chaperone in the ER to mediate unfolded protein response (UPR) and the pathogenesis of multiple myeloma (MM) is closely linked to dysregulated UPR. In this study, we aimed to determine the roles of gp96 in the initiation and progression of MM in vivo and in vitro. We generated a mouse model with over-expression of XBP1s and conditional deletion of gp96 in B cell compartment simultaneously to identify the roles of gp96 in the development of MM in vivo. Using a shRNA system, we silenced gp96 in multiple human MM cells and examined the effect of gp96 knockdown on MM cells by cell proliferation, cell cycle analysis, apoptosis assay, immunohistochemistry and human myeloma xenograft model. The anti-cancer activity of gp96 selective inhibitor, WS13 was evaluated by apoptosis assay and MTT assay. Genetic deletion of gp96 in XBP1s-Tg mice attenuates multiple myeloma. Silencing of gp96 causes severe compromise in human MM cell growth through inhibiting Wnt-LRP-survivin pathway. We also confirmed that knockdown of gp96 decreased human MM growth in a murine xenograft model. The targeted gp96 inhibitor induced apoptosis and blocked MM cell growth, but did not induce apoptosis in pre-B leukemic cells. We have demonstrated that myeloma growth is dependent on gp96 both genetically and pharmacologically. gp96 is essential for MM cell proliferation and survival, suggesting that gp96 is a novel therapeutic target for multiple myeloma.