PMID- 35148992
OWN - NLM
STAT- MEDLINE
DCOM- 20220415
LR  - 20220531
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 298
IP  - 3
DP  - 2022 Mar
TI  - Expression of gamma-glutamyltransferase 1 in glioblastoma cells confers 
      resistance to cystine deprivation-induced ferroptosis.
PG  - 101703
LID - S0021-9258(22)00143-0 [pii]
LID - 10.1016/j.jbc.2022.101703 [doi]
LID - 101703
AB  - Ferroptosis is an iron-dependent mode of cell death caused by excessive oxidative 
      damage to lipids. Lipid peroxidation is normally suppressed by glutathione 
      peroxidase 4, which requires reduced glutathione. Cystine is a major resource for 
      glutathione synthesis, especially in cancer cells. Therefore, cystine deprivation 
      or inhibition of cystine uptake promotes ferroptosis in cancer cells. However, 
      the roles of other molecules involved in cysteine deprivation-induced ferroptosis 
      are unexplored. We report here that the expression of gamma-glutamyltransferase 1 
      (GGT1), an enzyme that cleaves extracellular glutathione, determines the 
      sensitivity of glioblastoma cells to cystine deprivation-induced ferroptosis at 
      high cell density (HD). In glioblastoma cells expressing GGT1, pharmacological 
      inhibition or deletion of GGT1 suppressed the cell density-induced increase in 
      intracellular glutathione levels and cell viability under cystine deprivation, 
      which were restored by the addition of cysteinylglycine, the GGT product of 
      glutathione cleavage. On the other hand, cystine deprivation induced glutathione 
      depletion and ferroptosis in GGT1-deficient glioblastoma cells even at an HD. 
      Exogenous expression of GGT1 in GGT1-deficient glioblastoma cells inhibited 
      cystine deprivation-induced glutathione depletion and ferroptosis at an HD. This 
      suggests that GGT1 plays an important role in glioblastoma cell survival under 
      cystine-limited and HD conditions. We conclude that combining GGT inhibitors with 
      ferroptosis inducers may provide an effective therapeutic approach for treating 
      glioblastoma.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Hayashima, Kazuki
AU  - Hayashima K
AD  - Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto 
      University, Kyoto, Japan.
FAU - Katoh, Hironori
AU  - Katoh H
AD  - Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto 
      University, Kyoto, Japan. Electronic address: hirokato@pharm.kyoto-u.ac.jp.
LA  - eng
PT  - Journal Article
DEP - 20220208
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 48TCX9A1VT (Cystine)
RN  - EC 2.3.2.2 (gamma-Glutamyltransferase)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - *Brain Neoplasms/enzymology/genetics/metabolism
MH  - Cell Line, Tumor
MH  - *Cystine/deficiency/metabolism
MH  - *Ferroptosis
MH  - *Glioblastoma/enzymology/genetics/metabolism
MH  - Glutathione/metabolism
MH  - Humans
MH  - *gamma-Glutamyltransferase/biosynthesis/genetics
PMC - PMC8897698
OTO - NOTNLM
OT  - amino acid
OT  - cell death
OT  - cell metabolism
OT  - cell surface enzyme
OT  - glioblastoma
OT  - glutathione
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2022/02/13 06:00
MHDA- 2022/04/16 06:00
PMCR- 2022/02/08
CRDT- 2022/02/12 05:28
PHST- 2021/12/09 00:00 [received]
PHST- 2022/02/02 00:00 [revised]
PHST- 2022/02/03 00:00 [accepted]
PHST- 2022/02/13 06:00 [pubmed]
PHST- 2022/04/16 06:00 [medline]
PHST- 2022/02/12 05:28 [entrez]
PHST- 2022/02/08 00:00 [pmc-release]
AID - S0021-9258(22)00143-0 [pii]
AID - 101703 [pii]
AID - 10.1016/j.jbc.2022.101703 [doi]
PST - ppublish
SO  - J Biol Chem. 2022 Mar;298(3):101703. doi: 10.1016/j.jbc.2022.101703. Epub 2022 
      Feb 8.