Abstract
Expression of the heparan sulfate proteoglycan syndecan-1 is a hallmark of both normal and multiple myeloma (MM) plasma cells. Syndecan-1 could affect plasma cell fate by strengthening integrin-mediated adhesion via its core protein and/or by accommodating and presenting soluble factors via its HS side chains. Here, we show that inducible RNAi-mediated knockdown of syndecan-1 in human MM cells leads to reduced growth rates and a strong increase of apoptosis. Importantly, knockdown of EXT1, a copolymerase critical for HS chain biosynthesis, had similar effects. Using an innovative myeloma xenotransplantation model in Rag-2(-/-)gamma(c)(-/-) mice, we demonstrate that induction of EXT1 knockdown in vivo dramatically suppresses the growth of bone marrow localized myeloma. Our findings provide direct evidence that the HS chains of syndecan-1 are crucial for the growth and survival of MM cells within the bone marrow environment, and indicate the HS biosynthesis machinery as a potential treatment target in MM.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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DNA-Binding Proteins / genetics
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Doxycycline / administration & dosage
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Drug Delivery Systems
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Gene Targeting
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Heparitin Sulfate / metabolism
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Heparitin Sulfate / physiology*
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Humans
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Immunoglobulin gamma-Chains / genetics
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Mice
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Mice, Knockout
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Multiple Myeloma / drug therapy
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology*
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N-Acetylglucosaminyltransferases / antagonists & inhibitors
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N-Acetylglucosaminyltransferases / genetics*
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N-Acetylglucosaminyltransferases / physiology
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RNA, Small Interfering / pharmacology*
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Syndecan-1 / genetics
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Syndecan-1 / metabolism
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Xenograft Model Antitumor Assays
Substances
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DNA-Binding Proteins
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Immunoglobulin gamma-Chains
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RNA, Small Interfering
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Rag2 protein, mouse
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Sdc1 protein, mouse
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Syndecan-1
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Heparitin Sulfate
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N-Acetylglucosaminyltransferases
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exostosin-1
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Doxycycline