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Prepublished online as a Blood First Edition Paper on November 14, 2002; DOI 10.1182/blood-2002-09-2813.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2762-2769
NEOPLASIA
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
From the the Jerome Lipper Multiple Myeloma Center,
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA;
and Department of Medicine, Harvard Medical School, Boston, MA.
Multiple myeloma (MM) is characterized by clonal expansion of
malignant plasma cells in the bone marrow 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 soluble CD40L (sCD40L) or anti-CD40 monoclonal antibody (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 extracellular signal-regulated mitogen-activated
protein kinase (ERK), but not c-jun amino-terminal kinase
(JNK) or p38, in a dose- and time-dependent manner. Using pharmacologic inhibitors of PI3K and MEK, 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 nuclear
factor (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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