HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells

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

Research output: Contribution to journalArticle

154 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Autophagy
Leukemia
Drug Therapy
MAP Kinase Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Microtubule-Associated Proteins
1-Phosphatidylinositol 4-Kinase
Lysosomes
Neutralizing Antibodies
Pharmaceutical Preparations
Protein Kinases
Neoplasms
Therapeutics
Pharmacology
Light
Cell Line
Wounds and Injuries

Keywords

  • autophagy
  • drug resistance
  • ERK
  • HMGB1
  • PI3K

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Liu, L., Yang, M., Kang, R., Wang, Z., Zhao, Y., Yu, Y., ... 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

HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells. / Liu, L.; Yang, M.; Kang, R.; Wang, Z.; Zhao, Y.; Yu, Y.; Xie, M.; Yin, Xiao-Ming; Livesey, K. M.; Lotze, M. T.; Tang, D.; Cao, L.

In: Leukemia, Vol. 25, No. 1, 01.2011, p. 23-31.

Research output: Contribution to journalArticle

Liu, L, Yang, M, Kang, R, Wang, Z, Zhao, Y, Yu, Y, Xie, M, Yin, X-M, Livesey, KM, Lotze, MT, Tang, D & Cao, L 2011, 'HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells', Leukemia, vol. 25, no. 1, pp. 23-31. https://doi.org/10.1038/leu.2010.225
Liu, L. ; Yang, M. ; Kang, R. ; Wang, Z. ; Zhao, Y. ; Yu, Y. ; Xie, M. ; Yin, Xiao-Ming ; Livesey, K. M. ; Lotze, M. T. ; Tang, D. ; Cao, L. / HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells. In: Leukemia. 2011 ; Vol. 25, No. 1. pp. 23-31.
@article{9efb5af432884aa8ae9cf67c60da29f9,
title = "HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells",
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.",
keywords = "autophagy, drug resistance, ERK, HMGB1, PI3K",
author = "L. Liu and M. Yang and R. Kang and Z. Wang and Y. Zhao and Y. Yu and M. Xie and Xiao-Ming Yin and Livesey, {K. M.} and Lotze, {M. T.} and D. Tang and L. Cao",
year = "2011",
month = "1",
doi = "10.1038/leu.2010.225",
language = "English (US)",
volume = "25",
pages = "23--31",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells

AU - Liu, L.

AU - Yang, M.

AU - Kang, R.

AU - Wang, Z.

AU - Zhao, Y.

AU - Yu, Y.

AU - Xie, M.

AU - Yin, Xiao-Ming

AU - Livesey, K. M.

AU - Lotze, M. T.

AU - Tang, D.

AU - Cao, L.

PY - 2011/1

Y1 - 2011/1

N2 - 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.

AB - 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.

KW - autophagy

KW - drug resistance

KW - ERK

KW - HMGB1

KW - PI3K

UR - http://www.scopus.com/inward/record.url?scp=78651286142&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78651286142&partnerID=8YFLogxK

U2 - 10.1038/leu.2010.225

DO - 10.1038/leu.2010.225

M3 - Article

C2 - 20927132

AN - SCOPUS:78651286142

VL - 25

SP - 23

EP - 31

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 1

ER -