RETRACTED: 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and expression by the novel proteasome inhibitor NPI-0052 contributes to its TRAIL-enhanced apoptosis in cancer cells (Retracted Article. See vol 197, pg 4860, 2016)

被引：59

作者：

Baritaki, Stavroula ^{[1
]}

Suzuki, Eriko ^{[1
,3
]}

Umezawa, Kazuo ^{[3
]}

Spandidos, Demetrios A. ^{[4
]}

Berenson, James ^{[5
]}

Daniels, Tracy R. ^{[2
]}

Penichet, Manuel L. ^{[1
,2
]}

Jazirehi, Ali R. ^{[1
]}

Palladino, Michael ^{[6
]}

Bonavida, Benjamin ^{[1
]}

机构：

[1] Univ Calif Los Angeles, Dept Microbiol Mol Genet & Immunol, David Geffen Sch Med, Div Surg Oncol,Johnson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Surg, David Geffen Sch Med, Div Surg Oncol,Johnson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

[3] Keio Univ, Dept Appl Chem, Yokohama, Kanagawa 223, Japan

[4] Univ Crete, Fac Med, Dept Clin Virol, Iraklion, Greece

[5] Inst Myeloma & Bone Canc Res, W Hollywood, CA 90069 USA

[6] Nereus Pharmaceut Inc, San Diego, CA 92121 USA

来源：

JOURNAL OF IMMUNOLOGY | 2008年 / 180卷 / 09期

关键词：

D O I：

10.4049/jimmunol.180.9.6199

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-kappa B activity was involved in TRAIL sensitization as corroborated by the use of the NF-kappa B 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.

引用

页码：6199 / 6210

页数：12

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