PMID- 20686688
OWN - NLM
STAT- MEDLINE
DCOM- 20101028
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 5
IP  - 7
DP  - 2010 Jul 29
TI  - Role of endoplasmic reticulum stress in alpha-TEA mediated TRAIL/DR5 death 
      receptor dependent apoptosis.
PG  - e11865
LID - 10.1371/journal.pone.0011865 [doi]
LID - e11865
AB  - BACKGROUND: Alpha-TEA (RRR-alpha-tocopherol ether-linked acetic acid analog), a 
      derivative of RRR-alpha-tocopherol (vitamin E) exhibits anticancer actions in 
      vitro and in vivo in variety of cancer types. The objective of this study was to 
      obtain additional insights into the mechanisms involved in alpha-TEA induced 
      apoptosis in human breast cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: alpha-TEA 
      induces endoplasmic reticulum (ER) stress as indicated by increased expression of 
      CCAAT/enhancer binding protein homologous protein (CHOP) as well as by enhanced 
      expression or activation of specific markers of ER stress such as glucose 
      regulated protein (GRP78), phosphorylated alpha subunit of eukaryotic initiation 
      factor 2 (peIF-2alpha), and spliced XBP-1 mRNA. Knockdown studies using siRNAs to 
      TRAIL, DR5, JNK and CHOP as well as chemical inhibitors of ER stress and 
      caspase-8 showed that: i) alpha-TEA activation of DR5/caspase-8 induces an ER 
      stress mediated JNK/CHOP/DR5 positive amplification loop; ii) alpha-TEA 
      downregulation of c-FLIP (L) protein levels is mediated by JNK/CHOP/DR5 loop via 
      a JNK dependent Itch E3 ligase ubiquitination that further serves to enhance the 
      JNK/CHOP/DR5 amplification loop by preventing c-FLIP's inhibition of caspase-8; 
      and (iii) alpha-TEA downregulation of Bcl-2 is mediated by the ER stress 
      dependent JNK/CHOP/DR5 signaling. CONCLUSION: Taken together, ER stress plays an 
      important role in alpha-TEA induced apoptosis by enhancing DR5/caspase-8 
      pro-apoptotic signaling and suppressing anti-apoptotic factors c-FLIP and Bcl-2 
      via ER stress mediated JNK/CHOP/DR5/caspase-8 signaling.
FAU - Tiwary, Richa
AU  - Tiwary R
AD  - School of Biological Sciences/C0900, Department of Nutritional Sciences/A2703, 
      University of Texas at Austin, Austin, Texas, United States of America.
FAU - Yu, Weiping
AU  - Yu W
FAU - Li, Jing
AU  - Li J
FAU - Park, Sook-Kyung
AU  - Park SK
FAU - Sanders, Bob G
AU  - Sanders BG
FAU - Kline, Kimberly
AU  - Kline K
LA  - eng
GR  - P30 ES007784/ES/NIEHS NIH HHS/United States
GR  - T32 ES007247/ES/NIEHS NIH HHS/United States
GR  - T32 ES07247/ES/NIEHS NIH HHS/United States
GR  - ES007784/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100729
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (CASP8 and FADD-Like Apoptosis Regulating Protein)
RN  - 0 (CFLAR protein, human)
RN  - 0 (DDIT3 protein, human)
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (HSPA5 protein, human)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 3.4.22.- (Caspase 8)
RN  - JW7FJR3ZLY (2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy 
      acetic acid)
RN  - R0ZB2556P8 (Tocopherols)
SB  - IM
MH  - Apoptosis/*drug effects/genetics
MH  - Blotting, Western
MH  - CASP8 and FADD-Like Apoptosis Regulating Protein/genetics/metabolism
MH  - Caspase 8/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Chromatin Immunoprecipitation
MH  - Endoplasmic Reticulum/drug effects/*metabolism
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases/genetics/metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/genetics/metabolism
MH  - RNA Interference
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - TNF-Related Apoptosis-Inducing Ligand/genetics/*metabolism
MH  - Tocopherols/*pharmacology
MH  - Transcription Factor CHOP/genetics/metabolism
PMC - PMC2912340
COIS- Competing Interests: US and international patents on alpha-TEA are held by the 
      Research Development Foundation. Kimberly Kline and Bob G. Sanders are listed as 
      inventors. No commercial applications or financial gain have been realized.
EDAT- 2010/08/06 06:00
MHDA- 2010/10/29 06:00
PMCR- 2010/07/29
CRDT- 2010/08/06 06:00
PHST- 2010/05/24 00:00 [received]
PHST- 2010/07/07 00:00 [accepted]
PHST- 2010/08/06 06:00 [entrez]
PHST- 2010/08/06 06:00 [pubmed]
PHST- 2010/10/29 06:00 [medline]
PHST- 2010/07/29 00:00 [pmc-release]
AID - 10-PONE-RA-19270 [pii]
AID - 10.1371/journal.pone.0011865 [doi]
PST - epublish
SO  - PLoS One. 2010 Jul 29;5(7):e11865. doi: 10.1371/journal.pone.0011865.