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.

Abstract

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.

• Authors: Stavroula Baritaki, Eriko Suzuki, Kazuo Umezawa, Demetrios A Spandidos, James Berenson, Tracy R Daniels, Manuel L Penichet, Ali R Jazirehi, Michael Palladino, Benjamin Bonavida
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 180 Issue 9 Pg. 6199-210 (May 01 2008) ISSN: 0022-1767 [Print] United States
• PMID: 18424742 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Boronic Acids
• Lactones
• NF-kappa B
• Protease Inhibitors
• Pyrazines
• Pyrroles
• RNA, Messenger
• RNA, Small Interfering
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• YY1 Transcription Factor
• Bortezomib
• marizomib

Topics

• Apoptosis (drug effects, genetics)
• Boronic Acids (pharmacology)
• Bortezomib
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Hematopoietic Stem Cells (metabolism)
• Humans
• Lactones (adverse effects, pharmacology)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Neoplasms (drug therapy, metabolism)
• Protease Inhibitors (adverse effects, pharmacology)
• Pyrazines (pharmacology)
• Pyrroles (adverse effects, pharmacology)
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (biosynthesis, genetics)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Transcription, Genetic (drug effects)
• Up-Regulation (drug effects)
• YY1 Transcription Factor (antagonists & inhibitors, biosynthesis, genetics)