Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, China.
Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China.
Biomed Pharmacother. 2019 Apr;112:108714. doi: 10.1016/j.biopha.2019.108714. Epub 2019 Mar 2.
Changes in the expression and subcellular localization of high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule, have been implicated in tumorigenesis and tumor cell death in response to cancer therapy. Specifically, HMGB1 release has been shown to occur with a specific form of induced cell death known as necroptosis. In the present study, we examined the role of HMGB1 in the necroptosis of acute myeloid leukemia (AML) cells. In two AML cell lines and primary AML cells from two patients, etoposide induced necroptosis via cIAP1/2 degradation when caspase activity was inhibited by Z-VAD-fmk, but treatment with extracellular HMGB1 prevented this necroptosis. Interestingly, HMGB1 did not prevent the degradation of cIAP1/2, but rather activated the nuclear factor kappa B pathway. The results of the present study provide evidence that extracellular HMGB1 is not only an important DAMP molecule released by cells upon necrosis, but also a regulatory factor that prevents necroptosis in AML cells.
高迁移率族蛋白 B1（HMGB1）是一种损伤相关分子模式（DAMP）分子，其表达和亚细胞定位的变化与肿瘤发生和肿瘤细胞对癌症治疗的死亡反应有关。具体来说，已经表明 HMGB1 的释放与一种称为坏死性凋亡的特定形式的诱导细胞死亡有关。在本研究中，我们研究了 HMGB1 在急性髓系白血病（AML）细胞坏死性凋亡中的作用。在两种 AML 细胞系和来自两名患者的原代 AML 细胞中，当 caspase 活性被 Z-VAD-fmk 抑制时，依托泊苷通过 cIAP1/2 降解诱导坏死性凋亡，但用细胞外 HMGB1 处理可防止这种坏死性凋亡。有趣的是，HMGB1 并没有阻止 cIAP1/2 的降解，而是激活了核因子 kappa B 通路。本研究的结果提供了证据，表明细胞外 HMGB1 不仅是坏死细胞释放的重要 DAMP 分子，而且是防止 AML 细胞坏死性凋亡的调节因子。
