Blockade of deubiquitinase USP7 overcomes bortezomib resistance by suppressing NF‐κB signaling pathway in multiple myeloma
Blockade of deubiquitinase USP7 overcomes bortezomib resistance by suppressing NF‐κB signaling pathway in multiple myeloma
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阻断去泛素酶 USP7 通过抑制多发性骨髓瘤中的 NF-κB 信号通路克服硼替佐米耐药性
DOI：
10.1002/jlb.2a1017-420rr
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Kailin Xu
中科院分区：
文献类型：
--
作者：
Yao Yao;Yan Zhang;Min Shi;Yueyue Sun;Chong Chen;Mingshan Niu;Qi Zhang;Lingyu Zeng;Ruosi Yao;Hujun Li;Jiajia Yang;Zhenyu Li;Kailin Xu
硼替佐米（BTZ）治疗多发性骨髓瘤（MM）是有希望的；然而，耐药的出现给临床治疗带来了挑战。因此，迫切需要一种新的靶向治疗或探索BTZ耐药的机制。目前的数据显示，骨髓瘤中USP7的高表达是总生存期短和预后差的预测因子。敲除USP7显著抑制了集落的形成，即使在生长因子存在的情况下也能抑制BTZ抗性MM细胞的增殖，克服了BTZ抗性。基因敲除可显著抑制BTZ -耐药MM细胞小鼠的肿瘤生长，延长其存活时间。机制上，USP7敲除通过稳定ΙκΒα和阻断NF‐κB通路显著增加了对BTZ的敏感性。不出所料，转染siRNA敲低IκBα后，MM细胞恢复了对BTZ的抗性。重要的是，USP7抑制剂的使用也抑制了NF - κB的活化，并与BTZ联合引发了BTZ耐药MM细胞的协同抗肿瘤活性。综上所述，本研究为评估USP7单独或联合BTZ抑制以克服BTZ耐药并改善MM患者预后的临床方案提供了依据。
The treatment of multiple myeloma (MM) with bortezomib (BTZ) is promising; however, the emergence of resistance is challenging in the clinical treatment. Thus, a novel targeted treatment or exploring the mechanism underlying BTZ resistance is an urgent requisite. The current data showed that high expression of USP7 in myeloma was a predictor of short overall survival and poor outcome. USP7 knockout significantly suppressed the colony formation, inhibited the proliferation of BTZ‐resistant MM cells even in the presence of growth factors, and overcame BTZ resistance. The knockout markedly inhibited the tumor growth and prolonged the survival of mice bearing BTZ‐resistant MM cells. Mechanistically, USP7 knockout remarkably increased the sensitivity to BTZ by stabilizing ΙκΒα and blocking the NF‐κB pathway. Not surprisingly, when IκBα was knocked down by siRNA transfection, the MM cells restored the BTZ resistance. Importantly, usage of USP7 inhibitors also suppressed the activation of NF‐κB and combination with BTZ triggered the synergistic antitumor activity in BTZ‐resistant MM cells. Taken together, this study provides the rationale for clinical protocols evaluating USP7 inhibition, alone and in combination with BTZ, to overcome BTZ resistance and improve the patient outcome in MM.
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影响因子：
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作者：
Zhao, Guang-Yin;Lin, Zong-Wu;Lu, Chun-Lai;Gu, Jie;Yuan, Yun-Feng;Xu, Feng-Kai;Liu, Rong-Hua;Ge, Di;Ding, Jian-Yong
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影响因子：
20.3
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通讯作者：
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影响因子：
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通讯作者：
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影响因子：
20.3
作者：
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通讯作者：
Anderson, Kenneth C.
DOI：
10.1620/tjem.239.165
发表时间：
2016-07
期刊：
The Tohoku journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
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