HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells
HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells
复制标题
HMGB1诱导的自噬促进白血病细胞的化疗耐药性
DOI：
10.1038/leu.2010.225
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发表时间：
2011-01-01
期刊：
影响因子：
11.4
通讯作者：
Cao, L.
中科院分区：
文献类型：
--
作者：
Liu, L.;Yang, M.;Cao, L.
自噬是一种严格调控的溶酶体依赖性分解代谢途径，在调节癌症的发生和进展以及确定肿瘤细胞对抗癌治疗的反应中发挥着重要作用。然而，自噬在白血病中的作用仍然很大程度上未知。在这里，我们展示了高迁移率族盒 1 (HMGB1)，这是最具特征性的损伤相关分子模式，在化疗诱导的细胞毒性后从白血病细胞系中释放出来，并激活自噬以防止损伤。 HMGB1中和抗体治疗增加了白血病细胞对化疗的敏感性；然而，外源性 HMGB1 使这些细胞对药物诱导的细胞毒性更具抵抗力。此外，通过自噬标记物微管相关蛋白轻链 3-II 的表达增加、隔离体 1 (p62) 的降解和自噬体形成来评估，外源 HMGB1 增加了自噬。此外，磷酸肌醇3-激酶-III或细胞外信号调节激酶激酶丝裂原激活蛋白激酶激酶/细胞外信号调节蛋白激酶的敲低或药物抑制可抑制HMGB1诱导的自噬。综上所述，这些结果表明化疗后 HMGB1 的释放是自噬的关键调节因子，也是白血病治疗干预的潜在药物靶点。
Autophagy, a tightly regulated lysosome-dependent catabolic pathway, is important in the regulation of cancer development and progression and in determining the response of tumor cells to anticancer therapy. However, the role of autophagy in leukemia still remains largely unknown. Here we show that high-mobility group box 1 (HMGB1), the best characterized damage-associated molecular pattern, was released from leukemia cell lines after chemotherapy-induced cytotoxicity and activated autophagy to protect against injury. Treatment with HMGB1-neutralizing antibodies increased the sensitivity of leukemia cells to chemotherapy; whereas, exogenous HMGB1 rendered these cells more resistant to drug-induced cytotoxicity. Moreover, exogenous HMGB1 increased autophagy as evaluated by increased expression of the autophagic marker microtubule-associated protein light chain 3-II, degradation of sequestosome 1 (p62) and autophagosome formation. Furthermore, knockdown or pharmacological inhibition of either phosphoinositide 3-kinase-III or extracellular signal-regulated kinase kinase mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase inhibited HMGB1-induced autophagy. Taken together, these results suggest that HMGB1 release after chemotherapy is a critical regulator of autophagy and a potential drug target for therapeutic interventions in leukemia.