期刊
LEUKEMIA
卷 25, 期 1, 页码 23-31出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2010.225
关键词
HMGB1; autophagy; PI3K; ERK; drug resistance
资金
- National Natural Sciences Foundation of China [30571982, 30772353, 30973234, 30500485]
- Doctoral Program of Higher Education of China [20070533042]
- University of Pittsburgh
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/extra-cellular 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. Leukemia (2011) 25, 23-31; doi: 10.1038/leu.2010.225; published online 7 October 2010
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