HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells

L. Liu, M. Yang, R. Kang, Z. Wang, Y. Zhao, Y. Yu, M. Xie, X. Yin, K. M. Livesey, M. T. Lotze, D. Tang, L. Cao

Research output: Contribution to journalArticle

167 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)23-31
Number of pages9
JournalLeukemia
Volume25
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • ERK
  • HMGB1
  • PI3K
  • autophagy
  • drug resistance

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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  • Cite this

    Liu, L., Yang, M., Kang, R., Wang, Z., Zhao, Y., Yu, Y., Xie, M., Yin, X., Livesey, K. M., Lotze, M. T., Tang, D., & Cao, L. (2011). HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells. Leukemia, 25(1), 23-31. https://doi.org/10.1038/leu.2010.225