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Blood, 30 July 2009, Vol. 114, No. 5, pp. 1046-1052. Prepublished online as a Blood First Edition Paper on May 12, 2009; DOI 10.1182/blood-2009-01-199604. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-01-199604v1 114/5/1046    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Google Scholar Articles by Hideshima, T. Articles by Anderson, K. C. PubMed PubMed Citation Articles by Hideshima, T. Articles by Anderson, K. C. Related Collections Lymphoid Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Bortezomib induces canonical nuclear factor-B activation in multiple myeloma cells Teru Hideshima1, Hiroshi Ikeda1, Dharminder Chauhan1, Yutaka Okawa1, Noopur Raje1, Klaus Podar1, Constantine Mitsiades1, Nikhil C. Munshi2, Paul G. Richardson1, Ruben D. Carrasco1, and Kenneth C. Anderson1 1 Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and 2 VA Boston Healthcare System, Harvard Medical School, MA Bortezomib is a proteasome inhibitor with remarkable preclinical and clinical antitumor activity in multiple myeloma (MM) patients. The initial rationale for its use in MM was inhibition of nuclear factor (NF)-B activity by blocking proteasomal degradation of inhibitor of B (IB). Bortezomib inhibits inducible NF-B activity; however, its impact on constitutive NF-B activity in MM cells has not yet been defined. In this study, we demonstrate that bortezomib significantly down-regulated IB expression and triggered NF-B activation in MM cell lines and primary tumor cells from MM patients. Importantly, no inhibition of p65 (RelA) nuclear translocation was recognized after bortezomib treatment in a murine xenograft model bearing human MM cells. Bortezomib-induced NF-B activation was mediated via the canonical pathway. Moreover, other classes of proteasome inhibitors also induced IB down-regulation associated with NF-B activation. Molecular mechanisms whereby bortezomib induced IB down-regulation were further examined. Bortezomib triggered phosphorylation of IB kinase (IKKβ) and its upstream receptor-interacting protein 2, whereas IKKβ inhibitor MLN120B blocked bortezomib-induced IB down-regulation and NF-B activation, indicating receptor-interacting protein 2/IKKβ signaling plays crucial role in bortezomib-induced NF-B activation. Moreover, IKKβ inhibitors enhanced bortezomib-induced cytotoxicity. Our studies therefore suggest that bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-B activity in MM cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Bortezomib paradigm shift in myeloma David J. McConkey Blood 2009 114: 931-932. [Abstract] [Full Text] [PDF] This article has been cited by other articles: D. J. McConkey Bortezomib paradigm shift in myeloma Blood, July 30, 2009; 114(5): 931 - 932. [Abstract] [Full Text] [PDF]

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