Removal of syndecan-1 promotes TRAIL-induced apoptosis in myeloma cells.
Syndecan is the major transmembrane proteoglycan in cells. Of the four syndecans, syndecan-1 is the dominant form expressed in multiple myeloma and is an indicator of poor prognosis. In the current study, we observed that early TRAIL-induced apoptotic processes were accompanied by cleavage of syndecan-1 intracellular region, and explored the possibility whether removal of syndecan-1 promotes apoptotic processes. We found that syndecan-1 knockdown by specific small interfering RNA in multiple myeloma enhanced TRAIL-induced apoptosis, even though the expression of TRAIL receptors and several apoptosis-associated molecules was unaffected. The enhanced TRAIL-mediated apoptosis in syndecan-1-deficient cells was not due to a decrease in surface heparan sulfate or a reduction in TRAIL receptor endocytosis. The increase in TRAIL-induced cell death was accompanied by an elevated caspase-8 activation and an enhanced formation of death-inducing signaling complexes, which could be attributed to an increased expression of TRAIL receptor O-glycosylation enzyme in syndecan-1-deficient cells. We also found that in H9 lymphoma and Jurkat cells, knockdown of the predominant syndecan member also led to an increase in Fas ligand-induced apoptosis. Our results demonstrate that syndecan plays a negative role in death receptor-mediated cell death, suggesting potential application of syndecan downregulation in the treatment of myeloma in combination with TRAIL.
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 11221, Taiwan.
Yung-Hsuan
YH
Wu
Chen-Ying
CY
Yang
Wen-Li
WL
Chien
Kuo-I
KI
Lin
Ming-Zong
MZ
Lai
D017209:Apoptosis / Q000502:physiology*; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000276:immunology / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D047468:Immunoprecipitation; D009101:Multiple Myeloma / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D053668:Syndecan-1 / Q000276:immunology / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000378:metabolism*
D053418:Death Domain Receptor Signaling Adaptor Proteins; D034741:RNA, Small Interfering; C508241:SDC1 protein, human; D053668:Syndecan-1; D053221:TNF-Related Apoptosis-Inducing Ligand