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* Department of Microbiology, Immunology, and Molecular Genetics and
Department of Surgery, Division of Surgical Oncology, David Geffen School of Medicine, Johnson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095;
Department of Applied Chemistry, Keio University, Yokohama, Japan;
Department of Clinical Virology, Faculty of Medicine, University of Crete, Heraklion, Greece;
¶ Institute for Myeloma and Bone Cancer Research, West Hollywood, CA 90069; and
|| Nereus Pharmaceuticals, Inc., San Diego, CA 92121
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-
B activity was involved in TRAIL sensitization as corroborated by the use of the NF-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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Grants CA107023 and CA107023-02S1.
2 S.B. and E.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Benjamin Bonavida, Department of Microbiology, Immunology, and Molecular Genetics, University of California, 10833 Le Conte Avenue, A2-060 CHS, Los Angeles, CA 90095. E-mail address: bbonavida{at}mednet.ucla.edu
4 Abbreviations used in this paper: XIAP, X-linked inhibitor of apoptosis; IAP, inhibitor of apoptosis protein; MM, multiple myeloma; CT-L, chymotrypsin-like proteolytic activity; DR, death receptor; CFU-E, CFU-erythroid; BFU-E, burst-forming unit erythroid; CFU-GEMM, CFU granulocyte/erythrocyte/macrophage/megakaryocyte multilineage colony; siRNA, small interfering RNA; 2MAM-A3, 2-methoxyantimycin A3; YY1, Yin Yang 1; DHMEQ, dehydroxymethylepoxyquinomicin; DiOC6, 3,3'-dihexyloxacarbocyanine; qRT-PCR, quantitative RT-PCR.
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