PMID- 15208660
OWN - NLM
STAT- MEDLINE
DCOM- 20040909
LR  - 20091119
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 23
IP  - 37
DP  - 2004 Aug 19
TI  - Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize 
      apoptosis induced by TRAIL/APO2-L in human malignant tumor cells.
PG  - 6261-71
AB  - Death receptor 5 (DR5) is a receptor for tumor necrosis factor-related 
      apoptosis-inducing ligand (TRAIL). TRAIL is a promising candidate for cancer 
      therapeutics due to its ability to induce apoptosis selectively in cancer cells. 
      Here, we report that histone deacetylase inhibitors (HDACIs) such as trichostatin 
      A (TSA), sodium butyrate, and suberoylanilide hydroxamic acid (SAHA) upregulated 
      DR5 expression in various human malignant tumor cells. An RNase protection assay 
      demonstrated that HDACIs induced DR5 mRNA markedly but not that of other death 
      receptor family members in Jurkat cells. HDACIs increased DR5 mRNA and protein in 
      a dose- and time-dependent manner. We also show TSA increased DR5 promoter 
      activity using a luciferase promoter assay. Furthermore, we demonstrated that 
      HDACIs strongly sensitized exogenous soluble recombinant human TRAIL-induced 
      apoptosis synergistically in Jurkat and HL-60 cells that were tolerant to TRAIL 
      alone. The combined use of HDACIs and TRAIL in suboptimal concentrations induced 
      Bid cleavage and activation of caspase-8, -10, -3, and -9. Human recombinant 
      DR5/Fc chimera protein, zVAD-fmk pancaspase inhibitor, and caspase-8 and -10 
      inhibitors efficiently reduced apoptosis induced by cotreatment with HDACIs and 
      TRAIL. Furthermore, TSA did not significantly induce DR5 protein and HDACIs did 
      not enhance TRAIL-induced apoptosis in normal human peripheral blood mononuclear 
      cells. These results suggest that this combined treatment with HDACIs and TRAIL 
      is a promising strategy for new cancer therapeutics.
FAU - Nakata, Susumu
AU  - Nakata S
AD  - Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical 
      Science, Kyoto Prefectural University of Medicine, Kawaramcahi-Hirokoji, 
      Kamigyo-ku, Kyoto 602-8566, Japan.
FAU - Yoshida, Tatsushi
AU  - Yoshida T
FAU - Horinaka, Mano
AU  - Horinaka M
FAU - Shiraishi, Takumi
AU  - Shiraishi T
FAU - Wakada, Miki
AU  - Wakada M
FAU - Sakai, Toshiyuki
AU  - Sakai T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BH3 Interacting Domain Death Agonist Protein)
RN  - 0 (BID protein, human)
RN  - 0 (Carrier Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNFRSF10B protein, human)
RN  - 0 (TNFSF10 protein, human)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Apoptosis/*physiology
MH  - Apoptosis Regulatory Proteins
MH  - BH3 Interacting Domain Death Agonist Protein
MH  - Blotting, Western
MH  - Carrier Proteins/metabolism
MH  - Caspases/metabolism
MH  - Cell Line, Tumor
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/*pharmacology
MH  - *Histone Deacetylase Inhibitors
MH  - Humans
MH  - Hydrolysis
MH  - Membrane Glycoproteins/*physiology
MH  - Promoter Regions, Genetic
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand
MH  - Receptors, Tumor Necrosis Factor/genetics/*physiology
MH  - TNF-Related Apoptosis-Inducing Ligand
MH  - Tumor Cells, Cultured
MH  - Tumor Necrosis Factor-alpha/*physiology
MH  - Up-Regulation/*drug effects
EDAT- 2004/06/23 05:00
MHDA- 2004/09/10 05:00
CRDT- 2004/06/23 05:00
PHST- 2004/06/23 05:00 [pubmed]
PHST- 2004/09/10 05:00 [medline]
PHST- 2004/06/23 05:00 [entrez]
AID - 1207830 [pii]
AID - 10.1038/sj.onc.1207830 [doi]
PST - ppublish
SO  - Oncogene. 2004 Aug 19;23(37):6261-71. doi: 10.1038/sj.onc.1207830.