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Originally published In Press as doi:10.1074/jbc.M003965200 on January 29, 2001
J. Biol. Chem., Vol. 276, Issue 18, 14728-14736, May 4, 2001
Hyaluronic Acid Induces Survival and Proliferation of Human
Myeloma Cells through an Interleukin-6-mediated Pathway Involving the
Phosphorylation of Retinoblastoma Protein*
Thierry
Vincent ,
Michel
Jourdan ,
Man-Sun
Sy§,
Bernard
Klein , and
Nadir
Mechti ¶
From the INSERM Unité U475, 99 rue Puech Villa,
34197 Montpellier cedex 5, France and § Institute of
Pathology and Cancer Research Center, Case Western Reserve University,
School of Medicine, Cleveland, Ohio 44106-4943
Originating from a post-switch memory B cell or
plasma cell compartment in peripheral lymphoid tissues, malignant
myeloma cells accumulate in the bone marrow of patients with multiple myeloma. In this favorable microenvironment their growth and survival are dependent upon both soluble factors and physical cell-to-cell and
cell-to-extracellular matrix contacts. In this report we show that
hyaluronan (HA), a major nonprotein glycosaminoglycan component of the
extracellular matrix in mammalian bone marrow, is a survival and
proliferation factor for human myeloma cells. The effect of HA is
mainly mediated through a gp 80-interleukin 6 (IL-6) receptor pathway
by a CD44-independent mechanism, suggesting that HA retains and
concentrates IL-6 close to its site of secretion, thus favoring its
autocrine activity. In addition, we show that HA-mediated survival and
proliferation of myeloma cells is associated with a down-regulation in
the expression of p27kip1 cyclin-dependent kinase
inhibitor and a hyperphosphorylation of the retinoblastoma protein
(pRb). These data suggest that HA could be an important component in
the myeloma cell physiopathology in vivo by potentiating
autocrine and/or paracrine IL-6 activities.
*
This work was supported by grants from the Association pour
la Recherche contre le Cancer, the INSERM, the CNRS, the Federation des
Centres de Lutte contre le Cancer Comites de l'Herault et du Gard, the
Ligue Contre le Cancer, and the Federation pour la Recherche Medicale.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
¶
To whom correspondence should be addressed: INSERM Unité
U475, 99 rue Puech Villa, 34197 Montpellier cedex 5, France. Tel.: 4 67 63 62 71; Fax: 4 67 04 18 63; E-mail:
mechti@u475.montp.inserm.fr.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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