PMID- 26747710
OWN - NLM
STAT- MEDLINE
DCOM- 20160808
LR  - 20240326
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Print)
IS  - 0264-6021 (Linking)
VI  - 473
IP  - 6
DP  - 2016 Mar 15
TI  - Loss of neutral ceramidase protects cells from nutrient- and energy 
      -deprivation-induced cell death.
PG  - 743-55
LID - 10.1042/BJ20150586 [doi]
AB  - Sphingolipids are a family of lipids that regulate the cell cycle, 
      differentiation and cell death. Sphingolipids are known to play a role in the 
      induction of apoptosis, but a role for these lipids in necroptosis is largely 
      unknown. Necroptosis is a programmed form of cell death that, unlike apoptosis, 
      does not require ATP. Necroptosis can be induced under a variety of conditions, 
      including nutrient deprivation and plays a major role in ischaemia/reperfusion 
      injury to organs. Sphingolipids play a role in ischaemia/reperfusion injury in 
      several organs. Thus, we hypothesized that sphingolipids mediate 
      nutrient-deprivation-induced necroptosis. To address this, we utilized mouse 
      embryonic fibroblast (MEFs) treated with 2-deoxyglucose (2DG) and antimycin A 
      (AA) to inhibit glycolysis and mitochondrial electron transport. 2DG/AA treatment 
      of MEFs induced necroptosis as it was receptor- interacting protein (RIP)-1/3 
      kinase-dependent and caspase-independent. Ceramides, sphingosine (Sph) and 
      sphingosine 1-phosphate (S1P) were increased following 2DG/AA treatment. Cells 
      lacking neutral ceramidase (nCDase(-/-)) were protected from 2DG/AA. Although 
      nCDase(-/-) cells generated ceramides following 2DG/AA treatment, they did not 
      generate Sph or S1P. This protection was stimulus-independent as nCDase(-/-) 
      cells were also protected from endoplasmic reticulum (ER) stressors [tunicamycin 
      (TN) or thapsigargin (TG)]. nCDase(-/-) MEFs had higher autophagic flux and 
      mitophagy than wild-type (WT) MEFs and inhibition of autophagy sensitized them to 
      necroptosis. These data indicate that loss of nCDase protects cells from 
      nutrient- deprivation-induced necroptosis via autophagy, and clearance of damaged 
      mitochondria. Results suggest that nCDase is a mediator of necroptosis and might 
      be a novel therapeutic target for protection from ischaemic injury.
CI  - (c) 2016 Authors; published by Portland Press Limited.
FAU - Sundaram, Kumaran
AU  - Sundaram K
AD  - Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 
      40202, U.S.A.
FAU - Mather, Andrew R
AU  - Mather AR
AD  - University of South Carolina Medical School, Columbia, SC 29209, U.S.A.
FAU - Marimuthu, Subathra
AU  - Marimuthu S
AD  - Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 
      40202, U.S.A.
FAU - Shah, Parag P
AU  - Shah PP
AD  - Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 
      40202, U.S.A. James Graham Brown Cancer Center, University of Louisville, KY 
      40202, U.S.A.
FAU - Snider, Ashley J
AU  - Snider AJ
AD  - Department of Medicine, Stony Brook Cancer Center, Stony Brook University, NY 
      11794, U.S.A.  parallelNorthport Veterans Affairs Medical Center, Northport, NY 11768, 
      U.S.A.
FAU - Obeid, Lina M
AU  - Obeid LM
AD  - Department of Medicine, Stony Brook Cancer Center, Stony Brook University, NY 
      11794, U.S.A.  parallelNorthport Veterans Affairs Medical Center, Northport, NY 11768, 
      U.S.A.
FAU - Hannun, Yusuf A
AU  - Hannun YA
AD  - Department of Medicine, Stony Brook Cancer Center, Stony Brook University, NY 
      11794, U.S.A.
FAU - Beverly, Levi J
AU  - Beverly LJ
AD  - Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 
      40202, U.S.A. James Graham Brown Cancer Center, University of Louisville, KY 
      40202, U.S.A. Department of Medicine, University of Louisville, KY 40202, U.S.A.
FAU - Siskind, Leah J
AU  - Siskind LJ
AD  - Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 
      40202, U.S.A. James Graham Brown Cancer Center, University of Louisville, KY 
      40202, U.S.A. leah.siskind@louisville.edu.
LA  - eng
GR  - I01 BX000156/BX/BLRD VA/United States
GR  - P01 CA097132/CA/NCI NIH HHS/United States
GR  - R01 DK093462/DK/NIDDK NIH HHS/United States
GR  - R01 GM097741/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20160108
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Lysophospholipids)
RN  - 11118-72-2 (antimycin)
RN  - 26993-30-6 (sphingosine 1-phosphate)
RN  - 642-15-9 (Antimycin A)
RN  - 9G2MP84A8W (Deoxyglucose)
RN  - EC 3.5.1.23 (Asah2 protein, mouse)
RN  - EC 3.5.1.23 (Neutral Ceramidase)
RN  - NGZ37HRE42 (Sphingosine)
SB  - IM
MH  - Animals
MH  - Antimycin A/analogs & derivatives/pharmacology
MH  - Cell Death/drug effects/*physiology
MH  - Cells, Cultured
MH  - Deoxyglucose/pharmacology
MH  - Fibroblasts/*drug effects
MH  - Gene Deletion
MH  - Gene Expression Regulation, Enzymologic/*physiology
MH  - Lysophospholipids/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Neutral Ceramidase/genetics/*metabolism
MH  - Sphingosine/analogs & derivatives/metabolism
MH  - Up-Regulation
PMC - PMC5513154
MID - NIHMS769130
OTO - NOTNLM
OT  - autophagy flux
OT  - endoplasmic reticulum (ER) stress
OT  - mitophagy
OT  - necroptosis
OT  - neutral ceramidase
OT  - sphingolipids
EDAT- 2016/01/10 06:00
MHDA- 2016/08/09 06:00
PMCR- 2017/07/17
CRDT- 2016/01/10 06:00
PHST- 2015/05/21 00:00 [received]
PHST- 2016/01/08 00:00 [accepted]
PHST- 2016/01/10 06:00 [entrez]
PHST- 2016/01/10 06:00 [pubmed]
PHST- 2016/08/09 06:00 [medline]
PHST- 2017/07/17 00:00 [pmc-release]
AID - BJ20150586 [pii]
AID - 10.1042/BJ20150586 [doi]
PST - ppublish
SO  - Biochem J. 2016 Mar 15;473(6):743-55. doi: 10.1042/BJ20150586. Epub 2016 Jan 8.