Syndecan‐1 modulates β‐integrin‐dependent and interleukin‐6‐dependent functions in breast cancer cell adhesion, migration, and resistance to irradiation

Abstract

Syndecan-1 is a cell surface heparan sulfate proteoglycan with various biological functions relevant to tumor progression and inflammation, including cell-cell adhesion, cell-matrix interaction, and cytokine signaling driving cell proliferation and motility. Syndecan-1 is a prognostic factor in breast cancer, and has a predicitive value for neodadjuvant chemotherapy. It is still poorly understood how syndecan-1 integrates matrix-dependent and cytokine-dependent signaling processes in the tumor microenvironment. Here, we evaluated the potential role of syndecan-1 in modulating matrix-dependent breast cancer cell migration in the presence of interleukin-6, and its potential involvement in resistance to irradiation in vitro. MDA-MB-231 breast cancer cells were transiently transfected with syndecan-1 small interfering RNA or control reagents, and this was followed by stimulation with interleukin-6 or irradiation. Cellular responses were monitored by adhesion, migration and colony formation assays, as well as analysis of cell signaling. Syndecan-1 depletion increased cell adhesion to fibronectin. Increased migration on fibronectin was significantly suppressed by interleukin-6, and GRGDSP peptides inhibited both adhesion and migration. Interleukin-6-induced activation of focal adhesion kinase and reduction of constitutive nuclear factor kappaB signaling were decreased in syndecan-1-deficient cells. Focal adhesion kinase hyperactivation in syndecan-1-depleted cells was associated with dramatically reduced radiation sensitivity. We conclude that loss of syndecan-1 leads to enhanced activation of b 1 -integrins and focal adhesion kinase, thus increasing breast cancer cell adhesion, migration, and resistance to irradiation. Syndecan-1 deficiency also attenuates the modulatory effect of the inflammatory microenvironment constituent interleukin-6 on cancer cell migration.

A transmembrane C-terminal fragment of syndecan-1 is generated by the metalloproteinase ADAM17 and promotes lung epithelial tumor cell migration and lung metastasis formation

“…Modulation of a 5 b 1 integrins by syndecan-1 was also reported during focal adhesion formation and migration [18][19][20]. Interestingly, the latter pathway can either enhance or suppress these processes [18][19][20]. Further, activation of focal adhesion kinase (FAK) and Rho GTPase has been implicated in syndecan-1-mediated effects on cell migration [16,21].…”

“…In addition, syndecan-1 can act as regulator of a v b 3 and a v b 5 integrin activation [15,17]. Modulation of a 5 b 1 integrins by syndecan-1 was also reported during focal adhesion formation and migration [18][19][20]. Interestingly, the latter pathway can either enhance or suppress these processes [18][19][20].…”

Syndecan-1 and Its Expanding List of Contacts

“…Recent studies showed that sdc1 knockdown in breast cancer cells increased their migration rate on FNcoated surfaces in a manner that was dependent on a 5 b 1 -or a v -containing integrins. 66 Whether similar results would be seen if cells were grown on LN332-coated surfaces is unknown.…”

Syndecan-1, a Cell Surface Proteoglycan, Negatively Regulates Initial Leukocyte Recruitment to the Brain across the Choroid Plexus in Murine Experimental Autoimmune Encephalomyelitis

“…As highly glycosylated, sulfated molecules and, hence, negatively charged molecules, they have a large capacity to bind to other charged molecules such as cytokines and chemokines (2) and have been implicated in the presentation of cytokines to cells (3)(4)(5) and in the activation of integrin receptors (6)(7)(8). Syndecans are the best studied class of cell surface heparan sulfate proteoglycans (9); they exist in four different forms, syndecan 1-4, all of which consist of a core protein containing an ectodomain (extracellular domain), which carries the glycosylation sites, a transmembrane domain and a cytoplasmic domain.…”