PMID- 24039713
OWN - NLM
STAT- MEDLINE
DCOM- 20140610
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 9
DP  - 2013
TI  - Abrogated thioredoxin system causes increased sensitivity to TNF-alpha-induced 
      apoptosis via enrichment of p-ERK 1/2 in the nucleus.
PG  - e71427
LID - 10.1371/journal.pone.0071427 [doi]
LID - e71427
AB  - Thioredoxin (Trx) and thioredoxin reductase 1 (TR1) are among the major redox 
      regulators in mammalian cells and have a wide variety of roles, including removal 
      of intracellular reactive oxygen species (ROS) and prevention of cell death. 
      Tumor necrosis factor-alpha (TNF-alpha) induces cancer cell death. Although ROS have been 
      proposed to participate in this process, the role of the thioredoxin system in 
      TNF-alpha stimulated cell death remains unclear. We investigated the possibility that 
      the thioredoxin system protects against TNF-alpha-induced cancer cell death by 
      examining whether TR1/Trx1 status controls TNF-alpha-induced apoptosis in EMT6 murine 
      breast cancer cells. TR1-deficient cells were more sensitive to TNF-alpha than 
      control cells. Increased sensitivity to TNF-alpha was most pronounced in 
      Trx1-deficient cells. TNF-alpha-induced nuclear localization of phosphorylated ERK 
      1/2 (p-ERK 1/2) correlated with increased apoptosis in TR1- and Trx1-deficient 
      cells, suggesting a pro-apoptotic role for nuclear p-ERK 1/2 in TNF-alpha-induced 
      apoptosis. In addition, phosphoinositide 3-kinase (PI3K) inhibition dramatically 
      reduced TNF-alpha-stimulated apoptosis and nuclear localization of p-ERK 1/2. In 
      contrast, inhibition of ROS, MEK, JNK, or p38 did not significantly alter p-ERK 
      1/2 localization or apoptosis in TR1- and Trx1-deficient cells compared to 
      control cells. Further, NF-kappaB p65 localization was not changed in TR1- and 
      Trx1-deficient cells in response to TNF-alpha relative to control cells. Our data 
      suggest that the thioredoxin system plays a critical role in protecting against 
      TNF-alpha-induced apoptosis by regulating the levels of nuclear p-ERK 1/2 in a 
      PI3K-dependent manner.
FAU - Yoo, Min-Hyuk
AU  - Yoo MH
AD  - Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center 
      for Cancer Research, National Institutes of Health, Bethesda, Maryland, United 
      States of America.
FAU - Carlson, Bradley A
AU  - Carlson BA
FAU - Gladyshev, Vadim N
AU  - Gladyshev VN
FAU - Hatfield, Dolph L
AU  - Hatfield DL
LA  - eng
GR  - R37 GM065204/GM/NIGMS NIH HHS/United States
GR  - R01 AG021518/AG/NIA NIH HHS/United States
GR  - R01 CA080946/CA/NCI NIH HHS/United States
GR  - ImNIH/Intramural NIH HHS/United States
GR  - R01 GM061603/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20130906
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Chromones)
RN  - 0 (Morpholines)
RN  - 0 (NF-kappa B)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 52500-60-4 (Thioredoxins)
RN  - EC 1.8.1.9 (Thioredoxin Reductase 1)
RN  - EC 1.8.1.9 (Txnrd1 protein, mouse)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Animals
MH  - *Apoptosis
MH  - Cell Line, Tumor
MH  - Cell Nucleus/*enzymology
MH  - Cell Survival
MH  - Chromones/pharmacology
MH  - Extracellular Signal-Regulated MAP Kinases/*metabolism
MH  - Gene Knockdown Techniques
MH  - Mice
MH  - Morpholines/pharmacology
MH  - NF-kappa B/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Transport
MH  - Thioredoxin Reductase 1/genetics/*metabolism
MH  - Thioredoxins/genetics/*metabolism
MH  - Tumor Necrosis Factor-alpha/*physiology
PMC - PMC3765418
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/09/17 06:00
MHDA- 2014/06/11 06:00
PMCR- 2013/09/06
CRDT- 2013/09/17 06:00
PHST- 2013/03/27 00:00 [received]
PHST- 2013/06/27 00:00 [accepted]
PHST- 2013/09/17 06:00 [entrez]
PHST- 2013/09/17 06:00 [pubmed]
PHST- 2014/06/11 06:00 [medline]
PHST- 2013/09/06 00:00 [pmc-release]
AID - PONE-D-13-12870 [pii]
AID - 10.1371/journal.pone.0071427 [doi]
PST - epublish
SO  - PLoS One. 2013 Sep 6;8(9):e71427. doi: 10.1371/journal.pone.0071427. eCollection 
      2013.