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Blood, 14 May 2009, Vol. 113, No. 20, pp. 4894-4902. Prepublished online as a Blood First Edition Paper on March 12, 2009; DOI 10.1182/blood-2008-08-173948. This Article Full Text Full Text (PDF) Supplemental Table and Figure All Versions of this Article: blood-2008-08-173948v1 113/20/4894    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 Citing Articles via Google Scholar Google Scholar Articles by Hiruma, Y. Articles by Kurihara, N. Search for Related Content PubMed PubMed Citation Articles by Hiruma, Y. Articles by Kurihara, N. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Increased signaling through p62 in the marrow microenvironment increases myeloma cell growth and osteoclast formation Yuko Hiruma1, Tadashi Honjo1, Diane F. Jelinek2, Jolene J. Windle3, Jaekyoon Shin4, G. David Roodman1,5, and Noriyoshi Kurihara1 1 Medicine/Hem-Onc, University of Pittsburgh, PA; 2 Department of Immunology, Mayo Clinic, Rochester, MN; 3 Human and Molecular Genetics, Virginia Commonwealth University, Richmond; 4 School of Medicine, Sungkyunkwan University, Suwon, Korea; and 5 Medicine/Hem-Onc, VA Pittsburgh Healthcare System, PA Adhesive interactions between multiple myeloma (MM) cells and marrow stromal cells activate multiple signaling pathways including nuclear factor B (NF-B), p38 mitogen-activated protein kinase (MAPK), and Jun N-terminal kinase (JNK) in stromal cells, which promote tumor growth and bone destruction. Sequestosome-1 (p62), an adapter protein that has no intrinsic enzymatic activity, serves as a platform to facilitate formation of signaling complexes for these pathways. Therefore, we determined if targeting only p62 would inhibit multiple signaling pathways activated in the MM microenvironment and thereby decrease MM cell growth and osteoclast formation. Signaling through NF-B and p38 MAPK was increased in primary stromal cells from MM patients. Increased interleukin-6 (IL-6) production by MM stromal cells was p38 MAPK-dependent while increased vascular cell adhesion molecule-1 (VCAM-1) expression was NF-B–dependent. Knocking-down p62 in patient-derived stromal cells significantly decreased protein kinase C (PKC), VCAM-1, and IL-6 levels as well as decreased stromal cell support of MM cell growth. Similarly, marrow stromal cells from p62–/– mice produced much lower levels of IL-6, tumor necrosis factor- (TNF-), and receptor activator of NF-B ligand (RANKL) and supported MM cell growth and osteoclast formation to a much lower extent than normal cells. Thus, p62 is an attractive therapeutic target for MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Fulciniti, P. Tassone, T. Hideshima, S. Vallet, P. Nanjappa, S. A. Ettenberg, Z. Shen, N. Patel, Y.-t. Tai, D. Chauhan, et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma Blood, July 9, 2009; 114(2): 371 - 379. [Abstract] [Full Text] [PDF]

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