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 language | English (US) |
---|---|
Pages (from-to) | 23-31 |
Number of pages | 9 |
Journal | Leukemia |
Volume | 25 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2011 |
Externally published | Yes |
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Keywords
- autophagy
- drug resistance
- ERK
- HMGB1
- PI3K
ASJC Scopus subject areas
- Hematology
- Cancer Research
- Anesthesiology and Pain Medicine
Cite this
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 journal › Article
}
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 -