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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2761-2770. Prepublished online as a Blood First Edition Paper on November 26, 2003; DOI 10.1182/blood-2003-09-3037. This Article Full Text (PDF) All Versions of this Article: 2003-09-3037v1 103/7/2761    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dai, Y. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Dai, Y. Articles by Grant, S. Social Bookmarking                   What's this? Submitted September 4, 2003 Accepted November 17, 2003 Interruption of the NF-b pathway by Bay 11-7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells Yun Dai, Xin-Yan Pei, Mohamed Rahmani, Daniel H Conrad, Paul Dent, and Steven Grant* Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Biochemistry, Virginia Commonwealth University, Richmond, VA, USA; Department of Pharmacology, Virginia Commonwealth University, Richmond, VA, USA Department of Microbiology, Virginia Commonwealth University, Richmond, VA, USA Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, USA * Corresponding author; email: stgrant{at}hsc.vcu.edu. Interactions between pharmacologic NF-B inhibitors (e.g., Bay 11-7082, SN-50) and the checkpoint abrogator UCN-01 have been examined in human multiple myeloma (MM) cells. Exposure of U266 cells to Bay 11-7082 (Bay) in combination with UCN-01 resulted in abrogation of NF-B/DNA binding activity and synergistic induction of apoptosis. Comparable synergism was observed in other MM cell lines and patient-derived CD138+ cells, as well as between an inhibitory peptide of NF-B (SN50) and UCN-01. Bay/UCN-01-mediated lethality involved mitochondrial dysfunction, cleavage of caspases, and PARP degradation. While Bay modestly blocked UCN-01-induced ERK phosphorylation, co-administration activated JNK and cdc2/cdk1, and downregulated Mcl-1, XIAP and Bcl-xL. Transfection with a constitutively activated MEK1/GFP construct failed to block apoptosis induced by Bay/UCN-01 but significantly attenuated MEK inhibitor (U0126)/ UCN-01-induced lethality. Inhibition of JNK activation by SP600125 or D-JNKI1 peptide markedly reduced Bay/UCN-01-mediated mitochondrial dysfunction and apoptosis as well as downregulation of Mcl-1, XIAP and Bcl-xL, but not cdc2/cdk1 activation. Stable transfection of cells with dominant-negative caspase 9 dramatically diminished Bay/UCN-01 lethality without altering JNK and cdc2/cdk1 activation. Lastly, neither IL-6 nor fibronectin-mediated adherence conferred resistance to Bay/UCN-01-induced apoptosis. Together, these findings suggest that a strategy combining UCN-01 with disruption of the IKK/IB/NF-B pathway warrants attention in MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Zhang and L. M. Khachigian Injury-induced Platelet-derived Growth Factor Receptor-{alpha} Expression Mediated by Interleukin-1{beta} (IL-1{beta}) Release and Cooperative Transactivation by NF-{kappa}B and ATF-4: IL-1{beta} FACILITATES HDAC-1/2 DISSOCIATION FROM PROMOTER J. Biol. Chem., October 9, 2009; 284(41): 27933 - 27943. [Abstract] [Full Text] [PDF] S. A. Rushworth and D. J. 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