Syndecan-2 expression increases serum-withdrawal-induced apoptosis, mediated by re-distribution of Fas into lipid rafts, in stably transfected Swiss 3T3 cells

Villena, Joan; Mainez, Jèssica; Noguer, Oriol; Contreras, Héctor R.; Granés, Francesc; Reina, Manuel; Fabregat, Isabel; Vilaró, Senén

doi:10.1007/s10495-006-0193-7

Cited by 5 publications

(6 citation statements)

References 55 publications

(71 reference statements)

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“…Self-induction of syndecan-2 is consistent with previous data showing that apoptotic factors induce syndecan-2, whereas syndecan-2 drives the apoptotic response (8,12). Hence, on apoptotic stimulation, syndecan-2 expression may rapidly increase to adapt the normal cell response.…”

Section: Discussionsupporting

confidence: 91%

“…Thus, alterations of mechanisms that control cell death contribute to resistance to chemotherapy. Syndecan-2, a membrane heparan sulfate proteoglycan, was shown to modulate events related to the apoptotic response, such as Fas distribution into lipid rafts in fibroblasts (8,9). We have previously shown that syndecan-2 controls the induction of apoptosis in osteoblasts, modulating mitogen-activated protein kinase and protein kinase Cδ signaling (10,11).…”

Section: Introductionmentioning

confidence: 99%

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High Wnt Signaling Represses the Proapoptotic Proteoglycan syndecan-2 in Osteosarcoma Cells

et al. 2010

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Osteosarcoma is characterized by frequent relapse and metastatic disease associated with resistance to chemotherapy. We previously showed that syndecan-2 is a mediator of the antioncogenic effect of chemotherapeutic drugs. The purpose of this work was to elucidate molecular mechanisms responsible for the low expression of syndecan-2 in osteosarcoma. We compared the regulatory activity of cis-acting DNA sequences of the syndecan-2 gene in osteosarcoma and osteoblastic cell lines. We identified a DNA region that negatively regulates syndecan-2 transcription in the osteosarcoma cells. T-cell factors (TCF) bind to this sequence in vivo. Wnt3a stimulation, β-catenin activation, and TCF overexpression resulted in syndecan-2 repression, whereas Wnt inhibition using sFRP-1 increased syndecan-2 expression in U2OS cells. RhoA activation blunted the stimulatory effect of sFRP-1 on syndecan-2 transcription, whereas RhoA inhibition enhanced syndecan-2 expression. These results indicate that Wnt/β-catenin and Wnt/RhoA signaling contribute to syndecan-2 repression. The alteration of syndecan-2 expression in osteosarcoma cell lines also seemed to be related to a higher shedding, controlled by Wnt/RhoA. Conversely, syndecan-2 was found to activate its own expression in U2OS cells through RhoA inhibition. These data identify a molecular network that may contribute to the low expression of the proapoptotic proteoglycan syndecan-2 in osteosarcoma cells. The high activity of the canonical Wnt pathway in the different osteosarcoma cells induces a constitutive repression of syndecan-2 transcription, whereas Wnt/RhoA signaling blocks the amplification loop of syndecan-2 expression. Our results identify syndecan-2 as a Wnt target and bring new insights into a possible pathologic role of Wnt signaling in osteosarcoma. Cancer Res; 70(13); 5399-408. ©2010 AACR.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

High Wnt Signaling Represses the Proapoptotic Proteoglycan syndecan-2 in Osteosarcoma Cells

et al. 2010

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“…As shown in Figure 3B, the effect of brefeldin A on the translocation of Fas was probably due to the inhibition of secretion of HS proteoglycans (HSPGs) that contained the HS4C3-binding epitope. Recently, it has been demonstrated that Fas is redistributed from intracellular pools to lipid rafts on the cell surface in Swiss 3T3 cells overexpressing syndecan-2 [42]. However, the mechanism of this redistribution has not yet been clarified.…”

Section: Discussionmentioning

confidence: 99%

3-O-Sulfated Heparan Sulfate Recognized by the Antibody HS4C3 Contribute to the Differentiation of Mouse Embryonic Stem Cells via Fas Signaling

et al. 2012

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Maintenance of self-renewal and pluripotency in mouse embryonic stem cells (mESCs) is regulated by the balance between several extrinsic signaling pathways. Recently, we demonstrated that heparan sulfate (HS) chains play important roles in the maintenance and differentiation of mESCs by regulating extrinsic signaling. Sulfated HS structures are modified by various sulfotransferases during development. However, the significance of specific HS structures during development remains unclear. Here, we show that 3-O-sulfated HS structures synthesized by HS 3-O-sulfotransferases (3OSTs) and recognized by the antibody HS4C3 increase during differentiation of mESCs. Furthermore, expression of Fas on the cell surface of the differentiated cells also increased. Overexpression of the HS4C3-binding epitope in mESCs induced apoptosis and spontaneous differentiation even in the presence of LIF and serum. These data showed that the HS4C3-binding epitope was required for differentiation of mESCs. Up-regulation of the HS4C3-binding epitope resulted in the recruitment of Fas from the cytoplasm to lipid rafts on the cell surface followed by activation of Fas signaling. Indeed, the HS4C3-binding epitope interacted with a region that included the heparin-binding domain (KLRRRVH) of Fas. Reduced self-renewal capability in cells overexpressing 3OST resulted from the degradation of Nanog by activated caspase-3, which is downstream of Fas signaling, and was rescued by the inhibition of Fas signaling. We also found that knockdown of 3OST and inhibition of Fas signaling reduced the potential for differentiation into the three germ layers during embryoid body formation. This is the first demonstration that activation of Fas signaling is mediated by an increase in the HS4C3-binding epitope and indicates a novel signaling pathway for differentiation in mESCs.

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“…(11)(12)(13)(14) Syndecan-2-dependent signaling contributes to the control of caspasedependent and independent cell death, and consistently, mediates the anti-oncogenic effects of chemotherapeutic drugs in OS cells. (13,15,16) We showed that the expression of syndecan-2 is low in OS cell lines and tissues compared to normal osteoblasts, (15) suggesting that decreased cell response to apoptotic stress and chemoresistance may be related to alterations of syndecan-2 expression. We also showed that low syndecan-2 expression in OS cells is due, in part, to the high repressive activity of the Wnt/b-catenin/T-cell factor (TCF) pathway.…”

Section: Introductionmentioning

confidence: 83%

Targeted inhibition of T-cell factor activity promotes syndecan-2 expression and sensitization to doxorubicin in osteosarcoma cells and bone tumors in mice

Dieudonné

Marion

Marie

et al. 2012

Journal of Bone and Mineral Research

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Alterations of Wnt signaling appear to be involved in the pathogenesis of osteosarcoma, presenting mutations of adenomatous polyposis coli (APC) and epigenetic downregulation of Wnt inhibitory factor 1. However, the precise role of Wnt effectors in the bone cancer progression remains unclear. We previously showed that Wnt/b-catenin/T-cell factor (TCF) activation are responsible for the repression of syndecan-2, a key modulator of apoptosis and chemosensitivity in osteosarcoma cells, suggesting a role of Wnt signaling in chemoresistance. In this study, we investigated the functional relationship between syndecan-2, Wnt/b-catenin/TCF signaling and chemosensitivity in these cells. To this goal, we selected resistant osteosarcoma cells from sensitive human cell lines using repeated exposures to doxorubicin. In doxorubicin-responsive but not in doxorubicin-resistant-derived cells syndecan-2 expression was upregulated by doxorubicin treatment. Moreover, syndecan-2 overexpression restored the sensitivity to doxorubicin in resistantderived cells. We found that syndecan-2 induction by doxorubicin is forkhead box protein O3A (Foxo3a)-dependent. Foxo3a overexpression resulted in increased syndecan-2 expression in sensitive and resistant-derived cells. Doxorubicin modulated Foxo3a binding on syndecan-2 gene promoter and induced Foxo-dependent inhibition of Wnt/TCF activity. Conversely, b-catenin/TCF activation impaired syndecan-2 induction by doxorubicin, indicating that Wnt signaling is competing with the action of the cytotoxic drug. However, b-catenin was also found to be required for Foxo3a activity. Consistently, Dickkopf 1 (DKK1) and secreted frizzled-related protein 1 (sFRP-1) altered doxorubicin action in sensitive cells, whereas inhibition of TCF activity strongly decreased cell viability and increased sensitivity to doxorubicin in sensitive and resistant cells. TCF inhibition also increased the effect of doxorubicin treatment in an orthotopic bone tumor model in mice. Altogether, these data provide evidence that the repression of syndecan-2 by Wnt/b-catenin/TCF signaling contributes to the resistance of osteosarcoma cells to doxorubicin and suggest that TCF inhibition may represent a novel therapeutic strategy in osteosarcoma. ß

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Syndecan-2 expression increases serum-withdrawal-induced apoptosis, mediated by re-distribution of Fas into lipid rafts, in stably transfected Swiss 3T3 cells

Cited by 5 publications

References 55 publications

High Wnt Signaling Represses the Proapoptotic Proteoglycan syndecan-2 in Osteosarcoma Cells

High Wnt Signaling Represses the Proapoptotic Proteoglycan syndecan-2 in Osteosarcoma Cells

3-O-Sulfated Heparan Sulfate Recognized by the Antibody HS4C3 Contribute to the Differentiation of Mouse Embryonic Stem Cells via Fas Signaling

Targeted inhibition of T-cell factor activity promotes syndecan-2 expression and sensitization to doxorubicin in osteosarcoma cells and bone tumors in mice

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