PMID- 31236919
OWN - NLM
STAT- MEDLINE
DCOM- 20200608
LR  - 20200608
IS  - 1365-2141 (Electronic)
IS  - 0007-1048 (Print)
IS  - 0007-1048 (Linking)
VI  - 187
IP  - 1
DP  - 2019 Oct
TI  - SIRT3 deacetylase activity confers chemoresistance in AML via regulation of 
      mitochondrial oxidative phosphorylation.
PG  - 49-64
LID - 10.1111/bjh.16044 [doi]
AB  - Acute myeloid leukaemia (AML) cells possess metabolism profiles, such as higher 
      rates of oxidative phosphorylation and dependence on fatty acid oxidation for 
      survival, and are dependent on the sophisticated regulation of reactive oxygen 
      species (ROS) generation for survival, drug resistance and stemness maintenance. 
      We found that sensitivity of primary AML cells to cytarabine correlated with SOD2 
      acetylation and the ability of the drug to induce mitochondrial ROS. The SOD2 
      deacetylase, SIRT3, protected AML cells from chemotherapy as shown by inhibited 
      apoptosis via inhibited drug-induced production of mitochondrial ROS. SIRT3 
      significantly decreased nicotinamide adenine dinucleotide phosphate 
      (NADP)/reduced NADP ratio and increased reduced glutathione/oxidized glutathione 
      ratio. Furthermore, SIRT3 enhanced oxidative phosphorylation (OxPhos) in AML 
      cells under both basic and cytarabine-treated conditions. A xenograft mouse model 
      showed that SIRT3 overexpressing AML cells and patient-derived xenograft mice 
      bearing high SIRT3 deacetylase activity were more resistant to chemotherapy in 
      vivo. SIRT3 inhibitor displayed synergy with cytarabine to ablate AML cells in 
      vitro and in mouse models. Taken together, our study showed that SIRT3 is capable 
      of reprograming mitochondrial metabolism towards OxPhos and downregulating ROS 
      generation, which contribute to the chemoresistance of AML cells. SIRT3 can be 
      utilized as a potential therapeutic target to improve the anti-leukaemic efficacy 
      of standard chemotherapeutic agents for AML.
CI  - (c) 2019 The Authors. British Journal of Haematology published by British Society 
      for Haematology and John Wiley & Sons Ltd.
FAU - Ma, Jiao
AU  - Ma J
AUID- ORCID: 0000-0001-8097-2202
AD  - Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong 
      University School of Medicine, Shanghai, China.
FAU - Liu, Bin
AU  - Liu B
AD  - Department of Haematology, Changhai Hospital of the Second Military Medical 
      University, Shanghai, China.
AD  - Department of Respiratory Medicine, The People's Liberation Army General 
      Hospital, Shanghai, China.
FAU - Yu, Dan
AU  - Yu D
AD  - Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong 
      University School of Medicine, Shanghai, China.
FAU - Zuo, Yong
AU  - Zuo Y
AD  - Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong 
      University School of Medicine, Shanghai, China.
FAU - Cai, Rong
AU  - Cai R
AD  - Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong 
      University School of Medicine, Shanghai, China.
FAU - Yang, Jianmin
AU  - Yang J
AD  - Department of Haematology, Changhai Hospital of the Second Military Medical 
      University, Shanghai, China.
FAU - Cheng, Jinke
AU  - Cheng J
AD  - Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong 
      University School of Medicine, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190624
PL  - England
TA  - Br J Haematol
JT  - British journal of haematology
JID - 0372544
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Reactive Oxygen Species)
RN  - 04079A1RDZ (Cytarabine)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 1.15.1.1 (superoxide dismutase 2)
RN  - EC 3.5.1.- (SIRT3 protein, human)
RN  - EC 3.5.1.- (Sirtuin 3)
SB  - IM
EIN - Br J Haematol. 2020 Feb;188(4):586. PMID: 32037518
MH  - Acetylation
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Antimetabolites, Antineoplastic/pharmacology/*therapeutic use
MH  - Apoptosis/drug effects/physiology
MH  - Cytarabine/pharmacology/*therapeutic use
MH  - Drug Resistance, Neoplasm/physiology
MH  - Female
MH  - Humans
MH  - Leukemia, Myeloid, Acute/*drug therapy/enzymology/*metabolism/pathology
MH  - Male
MH  - Mice, SCID
MH  - Middle Aged
MH  - Mitochondria/metabolism
MH  - Oxidative Phosphorylation
MH  - Reactive Oxygen Species/metabolism
MH  - Sirtuin 3/*physiology
MH  - Superoxide Dismutase/metabolism
MH  - Tumor Cells, Cultured
MH  - Xenograft Model Antitumor Assays
PMC - PMC6790595
OTO - NOTNLM
OT  - AML
OT  - ROS
OT  - SIRT3
OT  - SOD2 acetylation
OT  - chemoresistance
COIS- There are no competing financial interests to declare.
EDAT- 2019/06/27 06:00
MHDA- 2020/06/09 06:00
PMCR- 2019/10/14
CRDT- 2019/06/26 06:00
PHST- 2019/02/18 00:00 [received]
PHST- 2019/04/15 00:00 [revised]
PHST- 2019/04/16 00:00 [accepted]
PHST- 2019/06/27 06:00 [pubmed]
PHST- 2020/06/09 06:00 [medline]
PHST- 2019/06/26 06:00 [entrez]
PHST- 2019/10/14 00:00 [pmc-release]
AID - BJH16044 [pii]
AID - 10.1111/bjh.16044 [doi]
PST - ppublish
SO  - Br J Haematol. 2019 Oct;187(1):49-64. doi: 10.1111/bjh.16044. Epub 2019 Jun 24.