PMID- 18424742
OWN - NLM
STAT- MEDLINE
DCOM- 20080604
LR  - 20211020
IS  - 0022-1767 (Print)
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 180
IP  - 9
DP  - 2008 May 1
TI  - Inhibition of Yin Yang 1-dependent repressor activity of DR5 transcription and 
      expression by the novel proteasome inhibitor NPI-0052 contributes to its 
      TRAIL-enhanced apoptosis in cancer cells.
PG  - 6199-210
AB  - TRAIL promotes apoptotic tumor cell death; however, TRAIL-resistant tumors need 
      to be sensitized to reverse resistance. Proteasome inhibitors potentiate TRAIL 
      apoptosis in vitro and in vivo and correlate with up-regulation of death receptor 
      5 (DR5) via an unknown mechanism. We hypothesized that the proteasome inhibitor 
      NPI-0052 inhibits the transcription repressor Yin Yang 1 (YY1) which regulates 
      TRAIL resistance and negatively regulates DR5 transcription. Treatment of PC-3 
      and Ramos cells with NPI-0052 (</=2.5 nM) and TRAIL sensitizes the tumor cells to 
      TRAIL-induced apoptosis. By comparison to bortezomib, a 400-fold less 
      concentration of NPI-0052 was used. NPI-0052 up-regulated DR5 reporter activity 
      and both surface and total DR5 protein expression. NPI-0052-induced inhibition of 
      NF-kappaB activity was involved in TRAIL sensitization as corroborated by the use 
      of the NF-kappaB inhibitor dehydroxymethylepoxyquinomicin. NPI-0052 inhibited YY1 
      promoter activity as well as both YY1 mRNA and protein expression. The direct 
      role of NPI-0052-induced inhibition of YY1 and up-regulation of DR5 in the 
      regulation of TRAIL sensitivity was demonstrated by the use of YY1 small 
      interfering RNA. The NPI-0052-induced sensitization to TRAIL involved activation 
      of the intrinsic apoptotic pathway and dysregulation of genes that regulate 
      apoptosis. The NPI-0052 concentrations used for TRAIL sensitization were not 
      toxic to human hematopoetic stem cells. The present findings demonstrate, for the 
      first time, the potential mechanism by which a proteasome inhibitor, like 
      NPI-0052, inhibits the transcription repressor YY1 involved in TRAIL resistance 
      and DR5 regulation. The findings also suggest the therapeutic application of 
      subtoxic NPI-0052 concentrations in combination with TRAIL/agonist DR4/DR5 mAbs 
      in the treatment of TRAIL-resistant tumors.
FAU - Baritaki, Stavroula
AU  - Baritaki S
AD  - Department of Microbiology, Immunology, and Molecular Genetics, Division of 
      Surgical Oncology, David Geffen School of Medicine, University of California-Los 
      Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
FAU - Suzuki, Eriko
AU  - Suzuki E
FAU - Umezawa, Kazuo
AU  - Umezawa K
FAU - Spandidos, Demetrios A
AU  - Spandidos DA
FAU - Berenson, James
AU  - Berenson J
FAU - Daniels, Tracy R
AU  - Daniels TR
FAU - Penichet, Manuel L
AU  - Penichet ML
FAU - Jazirehi, Ali R
AU  - Jazirehi AR
FAU - Palladino, Michael
AU  - Palladino M
FAU - Bonavida, Benjamin
AU  - Bonavida B
LA  - eng
GR  - R01 CA107023/CA/NCI NIH HHS/United States
GR  - CA 107023-02S1/CA/NCI NIH HHS/United States
GR  - CA 107023/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Boronic Acids)
RN  - 0 (Lactones)
RN  - 0 (NF-kappa B)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Pyrazines)
RN  - 0 (Pyrroles)
RN  - 0 (RNA, Messenger)
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  - 0 (YY1 Transcription Factor)
RN  - 69G8BD63PP (Bortezomib)
RN  - 703P9YDP7F (marizomib)
SB  - IM
MH  - Apoptosis/*drug effects/genetics
MH  - Boronic Acids/pharmacology
MH  - Bortezomib
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Drug Screening Assays, Antitumor
MH  - Hematopoietic Stem Cells/metabolism
MH  - Humans
MH  - Lactones/adverse effects/*pharmacology
MH  - NF-kappa B/antagonists & inhibitors/metabolism
MH  - Neoplasms/*drug therapy/metabolism
MH  - Protease Inhibitors/adverse effects/*pharmacology
MH  - Pyrazines/pharmacology
MH  - Pyrroles/adverse effects/*pharmacology
MH  - RNA, Messenger/genetics/metabolism
MH  - RNA, Small Interfering/genetics
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/*biosynthesis/genetics
MH  - TNF-Related Apoptosis-Inducing Ligand/*pharmacology
MH  - Transcription, Genetic/drug effects
MH  - Up-Regulation/*drug effects
MH  - YY1 Transcription Factor/antagonists & inhibitors/*biosynthesis/genetics
PMC - PMC3747671
MID - NIHMS509079
EDAT- 2008/04/22 09:00
MHDA- 2008/06/05 09:00
PMCR- 2013/08/20
CRDT- 2008/04/22 09:00
PHST- 2008/04/22 09:00 [pubmed]
PHST- 2008/06/05 09:00 [medline]
PHST- 2008/04/22 09:00 [entrez]
PHST- 2013/08/20 00:00 [pmc-release]
AID - 180/9/6199 [pii]
AID - 10.4049/jimmunol.180.9.6199 [doi]
PST - ppublish
SO  - J Immunol. 2008 May 1;180(9):6199-210. doi: 10.4049/jimmunol.180.9.6199.