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Molecular Targets for Therapy

HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells

Leukemia volume 25, pages 23–31 (2011)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by grants from The National Natural Sciences Foundation of China (30571982, 30772353, 30973234 to LC, 30500485 to DT), Doctoral Program of Higher Education of China (20070533042 to LC), and a grant from University of Pittsburgh (DT).

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Author notes

  1. L Liu, M Yang and R Kang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China

    L Liu, M Yang, R Kang, Z Wang, Y Zhao, Y Yu, M Xie & L Cao

  2. Department of Pediatrics, The First Affiliated Hospital of Nanhua University, Hengyang, Hunan, People's Republic of China

    X Yin

  3. Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    K M Livesey, M T Lotze & D Tang

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Correspondence to D Tang or L Cao.

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Liu, L., Yang, M., Kang, R. et al. HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells. Leukemia 25, 23–31 (2011). https://doi.org/10.1038/leu.2010.225

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