PMID- 31347748
OWN - NLM
STAT- MEDLINE
DCOM- 20191025
LR  - 20210618
IS  - 1365-2184 (Electronic)
IS  - 0960-7722 (Print)
IS  - 0960-7722 (Linking)
VI  - 52
IP  - 5
DP  - 2019 Sep
TI  - Caspase-3-mediated GSDME activation contributes to cisplatin- and 
      doxorubicin-induced secondary necrosis in mouse macrophages.
PG  - e12663
LID - 10.1111/cpr.12663 [doi]
LID - e12663
AB  - OBJECTIVE: Induction of secondary necrosis/pyroptosis contributes to the toxicity 
      of chemotherapeutic drugs, in which gasdermin E (GSDME) plays critical roles. 
      This study aimed to explore whether GSDME is involved in mediating the cytotoxic 
      effects of cisplatin and doxorubicin on mouse macrophages. METHODS: RAW 264.7 
      cells and bone marrow-derived macrophages (BMDMs) were treated with cisplatin or 
      doxorubicin. Propidium iodide staining was used to assay necrosis, and 
      immunoblotting was performed to detect protein expression. GSDME was knocked down 
      by using small interfering RNA. Mice were injected intraperitoneally to evaluate 
      toxicity to macrophages in vivo. Flow cytometry and immunofluorescence microscopy 
      were adopted to analyse phenotypes of peritoneal cells. Cytokine levels were 
      assayed by cytometric bead array. RESULTS: Both cisplatin and doxorubicin 
      dose-dependently induced necrosis in mouse RAW 264.7 macrophages and BMDMs. 
      Accompanying this, multiple caspases were activated, concomitant with the 
      cleavage of poly (ADP-ribose) polymerase. Consistent with caspase-3 activation, 
      GSDME was cleaved to generate its N-terminal fragment (GSDME-NT), thus leading to 
      secondary necrosis/pyroptosis. Inhibition of caspase-3 significantly attenuated 
      the generation of GSDME-NT concurrently with decreased necrosis in macrophages. 
      GSDME knockdown also evidently decreased the necrosis in RAW 264.7 and BMDMs. 
      Besides, cisplatin administration depleted peritoneal macrophages in mice, which 
      was associated with caspase-3 activation and GSDME-NT generation. Consistent with 
      the macrophage depletion, cisplatin administration significantly decreased 
      survival of mice with bacterial infection. CONCLUSION: Chemotherapeutic cisplatin 
      and doxorubicin exerted their cytotoxicity on macrophages partly by inducing 
      caspase-3/GSDME-mediated secondary necrosis.
CI  - (c) 2019 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.
FAU - Mai, Feng-Yi
AU  - Mai FY
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou, China.
FAU - He, Pengyan
AU  - He P
AD  - School of Medicine, Sun Yat-Sen University, Shenzhen, China.
FAU - Ye, Jie-Zhou
AU  - Ye JZ
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou, China.
FAU - Xu, Li-Hui
AU  - Xu LH
AD  - Department of Cell Biology, College of Life Science and Technology, Jinan 
      University, Guangzhou, China.
FAU - Ouyang, Dong-Yun
AU  - Ouyang DY
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou, China.
FAU - Li, Chen-Guang
AU  - Li CG
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou, China.
FAU - Zeng, Qiong-Zhen
AU  - Zeng QZ
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou, China.
FAU - Zeng, Chen-Ying
AU  - Zeng CY
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou, China.
FAU - Zhang, Cheng-Cheng
AU  - Zhang CC
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou, China.
FAU - He, Xian-Hui
AU  - He XH
AUID- ORCID: 0000-0001-7433-7392
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou, China.
FAU - Hu, Bo
AU  - Hu B
AD  - Department of Nephrology, the First Affiliated Hospital of Jinan University, 
      Guangzhou, China.
LA  - eng
GR  - 81673664/National Natural Science Foundation of China/
GR  - 81773965/National Natural Science Foundation of China/
GR  - 81873064/National Natural Science Foundation of China/
PT  - Journal Article
DEP - 20190726
PL  - England
TA  - Cell Prolif
JT  - Cell proliferation
JID - 9105195
RN  - 0 (Cytokines)
RN  - 0 (Gsdme protein, mouse)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, Estrogen)
RN  - 80168379AG (Doxorubicin)
RN  - EC 3.4.22.- (Caspase 3)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Caspase 3/*metabolism
MH  - Cisplatin/*pharmacology
MH  - Cytokines/metabolism
MH  - Doxorubicin/*pharmacology
MH  - Escherichia coli Infections/drug therapy/mortality/pathology/veterinary
MH  - Macrophages/cytology/drug effects/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Pyroptosis/*drug effects
MH  - RAW 264.7 Cells
MH  - RNA Interference
MH  - RNA, Small Interfering/metabolism
MH  - Receptors, Estrogen/antagonists & inhibitors/genetics/*metabolism
MH  - Survival Rate
PMC - PMC6797504
OTO - NOTNLM
OT  - caspase-3
OT  - chemotherapeutic drugs
OT  - gasdermin E
OT  - macrophages
OT  - secondary necrosis
COIS- The authors have no conflicts of interest to declare.
EDAT- 2019/07/28 06:00
MHDA- 2019/10/28 06:00
PMCR- 2019/07/26
CRDT- 2019/07/27 06:00
PHST- 2019/01/29 00:00 [received]
PHST- 2019/06/01 00:00 [revised]
PHST- 2019/06/27 00:00 [accepted]
PHST- 2019/07/28 06:00 [pubmed]
PHST- 2019/10/28 06:00 [medline]
PHST- 2019/07/27 06:00 [entrez]
PHST- 2019/07/26 00:00 [pmc-release]
AID - CPR12663 [pii]
AID - 10.1111/cpr.12663 [doi]
PST - ppublish
SO  - Cell Prolif. 2019 Sep;52(5):e12663. doi: 10.1111/cpr.12663. Epub 2019 Jul 26.