DAMP-mediated autophagy contributes to drug resistance.
Damage-associated molecular pattern molecules (DAMPs) are cellularly derived molecules that can initiate and perpetuate immune responses following trauma, ischemia and other types of tissue damage in the absence of pathogenic infection. High mobility group box 1 (HMGB1) is a prototypical DAMP and is associated with the hallmarks of cancer. Recently we found that HMGB1 release after chemotherapy treatment is a critical regulator of autophagy and a potential drug target for therapeutic interventions in leukemia. Overexpression of HMGB1 by gene transfection rendered leukemia cells resistant to cell death; whereas depletion or inhibition of HMGB1 and autophagy by RNA interference or pharmacological inhibitors increased the sensitivity of leukemia cells to chemotherapeutic drugs. HMGB1 release sustains autophagy as assessed by microtubule-associated protein 1 light chain 3 (LC3) lipidation, redistribution of LC3 into cytoplasmic puncta, degradation of p62 and accumulation of autophagosomes and autolysosomes. Moreover, these data suggest a role for HMGB1 in the regulation of autophagy through the PI3KC3-MEKERK: pathway, supporting the notion that HMGB1-induced autophagy promotes tumor resistance to chemotherapy.
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China.
Liying
L
Liu
Minghua
M
Yang
Rui
R
Kang
Zhuo
Z
Wang
Yiming
Y
Zhao
Yan
Y
Yu
Min
M
Xie
Xiaocheng
X
Yin
Kristen M
KM
Livesey
Michael T
MT
Loze
Daolin
D
Tang
Lizhi
L
Cao
D001343:Autophagy; D019008:Drug Resistance, Neoplasm; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000473:pathology; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051192:Receptors, Pattern Recognition / Q000378:metabolism*
D024243:HMGB1 Protein; D051192:Receptors, Pattern Recognition; D019869:Phosphatidylinositol 3-Kinases