Article

Removal of syndecan-1 promotes TRAIL-induced apoptosis in myeloma cells.

Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 11221, Taiwan.
The Journal of Immunology (Impact Factor: 5.36). 03/2012; 188(6):2914-21. DOI: 10.4049/jimmunol.1102065
Source: PubMed

ABSTRACT 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.

Full-text

Available from: Chen-Ying Yang, Jul 19, 2014
1 Follower
 · 
140 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Syndecan-1 (SDC1, synd, CD138) is the most widely studied member of four structurally related cell surface heparan sulfate proteoglycans (HSPG). Although SDC1 has been implicated in a wide range of biological functions, its altered expression often produces malignant phenotypes, which arise from increased cell proliferation and cell growth, cell survival, cell invasion and metastasis, and angiogenesis. Recent studies revealed much about the underlying molecular roles of SDC1 in these processes. The changes in SDC1 expression also have a direct impact on the clinical course of cancers, as evident by its prognostic significance. Accumulating evidence suggest that SDC1 is involved in stimulation of cancer stem cells (CSC) or tumor initiating cells (TIC) and this may affect disease relapse, and resistance to therapy. This review discusses the progress on the pro-tumorigenic role(s) of SDC1 and how these roles may impact the clinical aspect of the disease. Also discussed, are the current strategies for targeting SDC1 or its related signaling. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Critical Reviews in Oncology/Hematology 12/2014; 94(1). DOI:10.1016/j.critrevonc.2014.12.003 · 4.05 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human embryo invasion and implantation into the inner wall of the maternal uterus, the endometrium, is the pivotal process for a successful pregnancy. Whereas disruption of the endometrial epithelial layer was already correlated with the programmed cell death, the role of apoptosis of the subjacent endometrial stromal cells during implantation is indistinct. The aim was to clarify whether apoptosis plays a role in the stromal invasion and to characterize if the apoptotic susceptibility of endometrial stromal cells to embryonic stimuli is influenced by decidualization and Syndecan-1. Therefore, the immortalized human endometrial stromal cell line St-T1 was used to first generate a new cell line with a stable Syndecan-1 knock down (KdS1), and second to further decidualize the cells with progesterone. As a replacement for the ethically inapplicable embryo all cells were treated with the embryonic factors and secretion products interleukin-1β, interferon-γ, tumor necrosis factor-α, transforming growth factor-β1 and anti-Fas antibody to mimic the embryo contact. Detection of apoptosis was verified via Caspase ELISAs, PARP cleavage and Annexin V staining. Apoptosis-related proteins were investigated via antibody arrays and underlying signaling pathways were analyzed by Western blot. Non-decidualized endometrial stromal cells showed a resistance towards apoptosis which was rescinded by decidualization and Syndecan-1 knock down independent of decidualization. This was correlated with an altered expression of several pro- and anti-apoptotic proteins and connected to a higher activation of pro-survival Akt in non-differentiated St-T1 as an upstream mediator of apoptotis-related proteins. This study provides insight into the largely elusive process of implantation, proposing an important role for stromal cell apoptosis to successfully establish a pregnancy. The impact of Syndecan-1 in attenuating the apoptotic signal is particularly interesting in the light of an already described influence on pregnancy disorders and therefore might provide a useful clinical tool in the future to prevent pregnancy complications provoked by inadequate implantation.
    PLoS ONE 01/2015; 10(4):e0121103. DOI:10.1371/journal.pone.0121103 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in cancer cells without harming most normal cells. Currently, multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL (rhTRAIL) and agonistic antibodies that target death receptors (DRs) 4 or 5. It is encouraging that these products have shown a tolerated safety profile in early phase studies. However, their therapeutic potential is likely limited by the emergence of tumor drug resistance phenomena. Increasing evidence indicates that TRAIL DRs are deficient on the plasma membrane of some cancer cells despite their total protein expression. Notably, the lack of surface DR4/DR5 is sufficient to render cancers resistant to TRAIL-induced apoptosis, regardless of the status of other apoptosis signaling components. The current review highlights recent findings on the dynamic expression of TRAIL death receptors, including the regulatory roles of endocytosis, autophagy, and Ras GTPase-mediated signaling events. This information could aid in the identification of novel predictive biomarkers of tumor response as well as the development of combinational drugs to overcome or bypass tumor drug resistance to TRAIL receptor-targeted therapies. Published by Elsevier Ltd.
    Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy 03/2015; 8. DOI:10.1016/j.drup.2015.02.001 · 8.82 Impact Factor