PMID- 17652336
OWN - NLM
STAT- MEDLINE
DCOM- 20080118
LR  - 20071106
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Linking)
VI  - 28
IP  - 11
DP  - 2007 Nov
TI  - Thapsigargin sensitizes human melanoma cells to TRAIL-induced apoptosis by 
      up-regulation of TRAIL-R2 through the unfolded protein response.
PG  - 2328-36
AB  - We have previously reported that sensitivity of melanoma cells to tumor necrosis 
      factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis is largely 
      correlated with the levels of expression of TRAIL death receptors, in particular, 
      TRAIL-R2 on the cell surface. However, fresh melanoma isolates and melanoma 
      tissue sections express, in general, low levels of death receptors for TRAIL. We 
      show in this study that the endoplasmic reticulum stress inducer, thapsigargin 
      (TG), selectively up-regulated TRAIL-R2 and enhanced TRAIL-induced apoptosis in 
      melanoma cells. However, the TRAIL-R2 pathway did not appear to be involved in 
      induction of apoptosis by TG alone. Up-regulation of TRAIL-R2 appeared to be 
      cooperatively mediated by the inositol-requiring transmembrane kinase and 
      endonuclease 1alpha (IRE1alpha)- and activation of transcription factor 
      (ATF)-6-signaling pathways of the unfolded protein response (UPR) and the 
      transcription factor CCAAT/enhancer-binding protein-homologous protein (CHOP). 
      The latter played a critical role in the initial phase of the increase in 
      TRAIL-R2 as small interfering RNA (siRNA) knockdown of CHOP blocked up-regulation 
      of TRAIL-R2 only at a relatively early stage (16 h) after exposure to TG. In 
      contrast, IRE1alpha and ATF6 appeared to be crucial in maintaining the increased 
      levels of TRAIL-R2 in that siRNA knockdown of IRE1alpha or ATF6 had no effect on 
      the increase in TRAIL-R2 at the initial phase, but blocked TRAIL-R2 up-regulation 
      at a relatively late stage (36 h). Our results indicate that modulation of the 
      UPR may be useful in sensitizing melanoma cells to TRAIL-induced apoptosis by 
      up-regulation of TRAIL-R2.
FAU - Chen, Li Hua
AU  - Chen LH
AD  - Immunology and Oncology Unit, David Maddison Clinical Sciences Building, 
      Newcastle Misericordiae Hospital, Cnr. King & Watt Streets, Newcastle, New South 
      Wales 2300, Australia.
FAU - Jiang, Chen Chen
AU  - Jiang CC
FAU - Kiejda, Kelly A
AU  - Kiejda KA
FAU - Wang, Yu Fang
AU  - Wang YF
FAU - Thorne, Rick F
AU  - Thorne RF
FAU - Zhang, Xu Dong
AU  - Zhang XD
FAU - Hersey, Peter
AU  - Hersey P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070725
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (DNA Primers)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNFSF10 protein, human)
RN  - 67526-95-8 (Thapsigargin)
SB  - IM
MH  - Apoptosis/*drug effects/physiology
MH  - Base Sequence
MH  - Cell Line, Tumor
MH  - DNA Primers
MH  - Flow Cytometry
MH  - Humans
MH  - Melanoma/*pathology
MH  - Membrane Potentials
MH  - Protein Denaturation
MH  - RNA, Small Interfering
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/*physiology
MH  - Signal Transduction
MH  - TNF-Related Apoptosis-Inducing Ligand/*physiology
MH  - Thapsigargin/*pharmacology
MH  - Up-Regulation/*drug effects
EDAT- 2007/07/27 09:00
MHDA- 2008/01/19 09:00
CRDT- 2007/07/27 09:00
PHST- 2007/07/27 09:00 [pubmed]
PHST- 2008/01/19 09:00 [medline]
PHST- 2007/07/27 09:00 [entrez]
AID - bgm173 [pii]
AID - 10.1093/carcin/bgm173 [doi]
PST - ppublish
SO  - Carcinogenesis. 2007 Nov;28(11):2328-36. doi: 10.1093/carcin/bgm173. Epub 2007 
      Jul 25.