Lycorine Downregulates HMGB1 to Inhibit Autophagy and Enhances Bortezomib Activity in Multiple Myeloma.
Lycorine Downregulates HMGB1 to Inhibit Autophagy and Enhances Bortezomib Activity in Multiple Myeloma.
复制标题
Lycorine 下调 HMGB1 以抑制自噬并增强多发性骨髓瘤中硼替佐米的活性
作者：
Roy M;Liang L;Xiao X;Peng Y;Luo Y;Zhou W;Zhang J;Qiu L;Zhang S;Liu F;Ye M;Zhou W;Liu J
多发性骨髓瘤（MM）在很大程度上是不可治愈的和耐药的。新的治疗方法，如抑制自噬或合理的药物组合旨在克服这个问题。在这项研究中，我们发现石蒜碱表现出一个有前途的抗增殖活性对MM在体外和体内通过抑制自噬。我们确定了高迁移率族蛋白1（HMGB 1），一个重要的自噬调节因子，作为石蒜碱处理后最异常表达的蛋白质，并作为石蒜碱活性的关键介质。基因表达谱（GEP）分析显示HMGB 1的高表达与MM的不良预后相关。这种相关性在人骨髓CD 138+原代骨髓瘤细胞和MM细胞系中得到进一步证实。机制上，石蒜碱对HMGB 1的蛋白酶体降解抑制MEK-ERK的活化，从而降低Bcl-2的磷酸化，导致Bcl-2与Beclin-1的组成性缔合。此外，我们观察到硼替佐米耐药细胞中HMGB 1的表达更高，并且硼替佐米加石蒜碱的组合在体外和体内骨髓瘤模型中以及在使硼替佐米耐药细胞重新敏感中是高效的。这些观察结果表明石蒜碱作为一种有效的自噬抑制剂，并揭示石蒜碱单独或与硼替佐米组合是一种潜在的治疗策略。
Multiple myeloma (MM) is largely incurable and drug-resistant. Novel therapeutic approaches such as inhibiting autophagy or rational drug combinations are aimed to overcome this issue. In this study, we found that lycorine exhibits a promising anti-proliferative activity against MM in vitro and in vivo by inhibiting autophagy. We identified High mobility group box 1 (HMGB1), an important regulator of autophagy, as the most aberrantly expressed protein after lycorine treatment and as a critical mediator of lycorine activity. Gene expression profiling (GEP) analysis showed that higher expression of HMGB1 is linked with the poor prognosis of MM. This correlation was further confirmed in human bone marrow CD138+ primary myeloma cells and MM cell lines. Mechanistically, proteasomal degradation of HMGB1 by lycorine inhibits the activation of MEK-ERK thereby decreases phosphorylation of Bcl-2 resulting in constitutive association of Bcl-2 with Beclin-1. In addition, we observed higher HMGB1 expression in bortezomib resistant cells and the combination of bortezomib plus lycorine was highly efficient in vitro and in vivo myeloma models as well as in re-sensitizing resistant cells to bortezomib. These observations indicate lycorine as an effective autophagy inhibitor and reveal that lycorine alone or in combination with bortezomib is a potential therapeutic strategy.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
3.3
作者：
Carew JS;Kelly KR;Nawrocki ST
通讯作者：
Nawrocki ST
影响因子：
12.4
作者：
Kang R;Tang D;Schapiro NE;Livesey KM;Farkas A;Loughran P;Bierhaus A;Lotze MT;Zeh HJ
通讯作者：
Zeh HJ
DOI：
10.1158/1078-0432.ccr-13-0495
发表时间：
2013-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kang R;Zhang Q;Zeh HJ 3rd;Lotze MT;Tang D
通讯作者：
Tang D
DOI：
10.1182/asheducation-2011.1.184
发表时间：
2011-12-01
期刊：
HEMATOLOGY-AMERICAN SOCIETY HEMATOLOGY EDUCATION PROGRAM
影响因子：
--
作者：
Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.