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Prepublished online as a Blood First Edition Paper on November 14, 2002; DOI 10.1182/blood-2002-09-2813.
Submitted September 16, 2002
Accepted November 7, 2002
CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF- B signaling
Yu-Tzu Tai, Klaus Podar, Nicholas Mitsiades, Boris Lin, Constantine Mitsiades, Deepak Gupta, Masaharu Akiyama, Laurence Catley, Teru Hideshima, Nikhil C Munshi, Steven P Treon, and Kenneth C Anderson*
Department of Adult Oncology, The Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA, USA
* Corresponding author; email: kenneth_anderson{at}dfci.harvard.edu.
Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells in the bone marrow (BM) and their egress into peripheral blood with progression to plasma cell leukemia. Our previous study defined a functional role of CD40 activation in MM cell homing and migration. In this study, we examine signaling events mediating CD40-induced MM cell migration. We show that cross-linking CD40, using either sCD40L or anti-CD40 mAb, induces phosphatidylinositol-3-kinase (PI3K) activity and activates its downstream effector AKT in MM.1S cells. CD40 activation also activates the MAP kinase (MEK) pathway, evidenced by phosphorylation of ERK, but not JNK or p38, in a dose- and time-dependent manner. Using pharmacological inhibitors of PI3K and MEKK, as well as adenoviruses expressing dominant negative and constitutively expressed AKT, we demonstrate that PI3K and AKT activities are required for CD40-induced MM cell migration. In contrast, inhibition of ERK/MEK phosphorylation only partially (10-15%) prevents migration, suggesting only a minor role in regulation of CD40-mediated MM migration. We further demonstrate that CD40 induces NF- B activation as a downstream target of PI3K/AKT signaling, and that inhibition of NF-B signaling using specific inhibitors PS1145 and SN50 completely abrogates CD40-induced MM migration. Finally, we demonstrate that urokinase plasminogen activator (uPA), an NF-B target gene, is induced by CD40; and conversely, that uPA induction via CD40 is blocked by PI3K and NF-B inhibitors. Our data therefore indicate that CD40-induced MM cell migration is primarily mediated via activation of PI3K/AKT/NF-B signaling, and further suggest that novel therapies targeting this pathway may inhibit MM cell migration associated with progressive MM.
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