PMID- 34933679
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20211226
IS  - 1475-2867 (Print)
IS  - 1475-2867 (Electronic)
IS  - 1475-2867 (Linking)
VI  - 21
IP  - 1
DP  - 2021 Dec 21
TI  - Extracellular HMGB1 interacts with RAGE and promotes chemoresistance in acute 
      leukemia cells.
PG  - 700
LID - 10.1186/s12935-021-02387-9 [doi]
LID - 700
AB  - BACKGROUND: Nowadays, acute leukemia (AL) among children has favorable outcome, 
      yet some of them get refractory or relapse mainly due to drug resistance. 
      High-mobility group box 1 (HMGB1) has been proven to have a important role in 
      drug resistance via upregulation of autophagy after chemotherapy treatment in 
      acute leukemia. However, the mechanism how extracellular HMGB1 acts on AL cells 
      and leads to chemoresistance remains elusive. METHOD: CCK8 was used to examine 
      the toxicity of chemotherapeutic drug. Elisa was performed to detect the release 
      of HMGB1. Western blot and mRFP-GFP-LC3 adenoviral particles as well as 
      transmission electron microscopy were used to detect the autophagy flux. Western 
      blot and flow cytometry were applied to evaluate the apoptosis. qPCR and western 
      blot were conducted to detect the expression of drug efflux protein. Lentivirus 
      infection was applied to knock down RAGE. In addition, T-ALL NOD/SCID mice 
      xenograft model was used to observe the effect of inhibiting HMGB1/RAGE axis. 
      RESULTS: We found that extracellular HMGB1 do upregulate autophagy and in the 
      meantime downregulate apoptosis, primarily through interaction with receptor for 
      advanced glycation end products (RAGE). Suppression of RAGE by RNA interference 
      alleviated the level of autophagy and enhanced apoptosis. What's more, HMGB1/RAGE 
      induced autophagy was associated with the activation of ERK1/2 and decreased 
      phosphorylation of mammalian target of rapamycin (mTOR), while HMGB1/RAGE limited 
      apoptosis in a Bcl-2-regulated way mediated by P53. On the other hand, we found 
      that HMGB1/RAGE activated the NF-kappaB pathway and promoted the expression of 
      P-glycation protein (P-gp) as well as multidrug resistance-associated protein 
      (MRP), both are ATP-binding cassette transporters. In vivo experiment, we found 
      that blocking HMGB1/RAGE axis do have a mild pathological condition and a better 
      survival in T-ALL mice. CONCLUSION: HMGB1/RAGE have a important role in drug 
      resistance after chemotherapy treatment, mainly by regulating autophagy and 
      apoptosis as well as promoting the expression of drug efflux protein such as P-gp 
      and MRP. HMGB1/RAGE might be a promising target to cure AL, especially for those 
      met with relapse and refractory.
CI  - (c) 2021. The Author(s).
FAU - Lai, Weixin
AU  - Lai W
AD  - Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene 
      Regulation, Guangzhou, People's Republic of China.
AD  - Department of Paediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen 
      University, 107 Yanjiang West Road, Guangzhou, 510120, Guangdong, People's 
      Republic of China.
FAU - Li, Xinyu
AU  - Li X
AD  - Department of Paediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen 
      University, 107 Yanjiang West Road, Guangzhou, 510120, Guangdong, People's 
      Republic of China.
FAU - Kong, Qian
AU  - Kong Q
AD  - Department of Pediatrics, The Third Affiliated Hospital of Sun Yat-Sen 
      University, Guangzhou, People's Republic of China.
FAU - Chen, Han
AU  - Chen H
AD  - Department of Paediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen 
      University, 107 Yanjiang West Road, Guangzhou, 510120, Guangdong, People's 
      Republic of China.
FAU - Li, Yunyao
AU  - Li Y
AD  - Department of Paediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen 
      University, 107 Yanjiang West Road, Guangzhou, 510120, Guangdong, People's 
      Republic of China.
FAU - Xu, Lu-Hong
AU  - Xu LH
AD  - Department of Paediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen 
      University, 107 Yanjiang West Road, Guangzhou, 510120, Guangdong, People's 
      Republic of China.
FAU - Fang, Jianpei
AU  - Fang J
AUID- ORCID: 0000-0002-5389-797X
AD  - Department of Paediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen 
      University, 107 Yanjiang West Road, Guangzhou, 510120, Guangdong, People's 
      Republic of China. fjianpei@163.com.
LA  - eng
GR  - SCE111DS/Bejing Bethune Chartfable Foundation/
PT  - Journal Article
DEP - 20211221
PL  - England
TA  - Cancer Cell Int
JT  - Cancer cell international
JID - 101139795
PMC - PMC8693501
OTO - NOTNLM
OT  - Acute leukemia
OT  - Apoptosis
OT  - Autophagy
OT  - Drug efflux protein
OT  - Drug-resistance
OT  - HMGB1
OT  - RAGE
COIS- The authors declare that they have no competing interests.
EDAT- 2021/12/23 06:00
MHDA- 2021/12/23 06:01
PMCR- 2021/12/21
CRDT- 2021/12/22 05:35
PHST- 2021/03/20 00:00 [received]
PHST- 2021/12/01 00:00 [accepted]
PHST- 2021/12/22 05:35 [entrez]
PHST- 2021/12/23 06:00 [pubmed]
PHST- 2021/12/23 06:01 [medline]
PHST- 2021/12/21 00:00 [pmc-release]
AID - 10.1186/s12935-021-02387-9 [pii]
AID - 2387 [pii]
AID - 10.1186/s12935-021-02387-9 [doi]
PST - epublish
SO  - Cancer Cell Int. 2021 Dec 21;21(1):700. doi: 10.1186/s12935-021-02387-9.