Abstract
In this study we demonstrate that tumor necrosis factor α (TNFα) triggers only modest proliferation, as well as p44/p42 mitogen-activated protein kinase (MAPK) and NF-κB activation, in MM.1S multiple myeloma (MM) cells. TNFα also activates NF-κB and markedly upregulates (fivefold) secretion of interleukin-6 (IL-6), a myeloma growth and survival factor, in bone marrow stromal cells (BMSCs). TNFα in both a dose and time dependent fashion induced expression of CD11a (LFA-1), CD54 (intercellular adhesion molecule-1, ICAM-1), CD106 (vascular cell adhesion molecule-1, VCAM-1), CD49d (very late activating antigen-4, VLA-4), and/or MUC-1 on MM cell lines; as well as CD106 (VCAM-1) and CD54 (ICAM-1) expression on BMSCs. This resulted in increased (2–4-fold) per cent specific binding of MM cells to BMSCs, with related IL-6 secretion. Importantly, the proteasome inhibitor PS-341 abrogated TNFα-induced NF-κB activation, induction of ICAM-1 or VCAM-1, and increased adhesion of MM cells to BMSCs. Agents which act to inhibit TNFα may therefore abrogate the paracrine growth and survival advantage conferred by MM cell adhesion in the BM microenvironment.
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Supported by National Institutes of Health Grant PO-1 78378 and the Doris Duke Distinguished Clinical Research Scientist Award to KC Anderson.
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Hideshima, T., Chauhan, D., Schlossman, R. et al. The role of tumor necrosis factor α in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene 20, 4519–4527 (2001). https://doi.org/10.1038/sj.onc.1204623
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DOI: https://doi.org/10.1038/sj.onc.1204623
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