Supplementary Materialsoncotarget-08-35804-s001

Supplementary Materialsoncotarget-08-35804-s001. the FAK/c-Src/ERK/STAT3/survivin pathway. Used together, these results suggest that SJFα extracellular galectin-1 contributes to cancer progression and doxorubicin SJFα resistance in TNBC cells. These effects appear to be mediated by galectin-1-induced up-regulation of the integrin 1/FAK/c-Src/ERK/STAT3/survivin pathway. Our results imply that extracellular galectin-1 has potential as a therapeutic target for triple-negative breast cancer. gene, was first identified as a -galactoside binding protein [4]. Galectin-1 has a conserved carbohydrate-recognition domain (CRD) consisting of about 130 amino acids that mediates binding to carbohydrate-rich regions of cell surface proteins [4, 5]. Moreover, galectin-1 is involved in cell transformation via direct interactions with cell surface oncogenic proteins such as integrins, laminin, and fibronectin, leading to subsequent cancer progression [6C8]. In addition, many studies have investigated the function of galectin-1 in the immunosuppressive mechanisms of human melanoma [9], neuroblastoma [10], and pancreatic carcinoma [11]. However, few reports have investigated the potential of galectin-1 as an extracellular therapeutic target, primarily because galectin-1 is predominantly a secretory protein. Therefore, we were motivated to investigate the potential of galectin-1 as a TNBC-specific extracellular therapeutic target molecule, even though galectin-1 is a typical secretory protein. Integrins are typical cell adhesion receptors related to cell proliferation, migration, invasion, and adhesion in various cancer cells [12C15]. The integrin family consists of 24 heterodimeric groups. The subunit determines the binding specificity of a given integrin to its cognate ligands, whereas the subunit drives numerous downstream signaling through interactions with the cytoskeleton [16]. Interestingly, the integrin 1 subunit has been reported to bind galectin-1 directly and to activate cytoskeletal-associated focal adhesion kinase (FAK) [7]. Activation of FAK, in turn, induces downstream c-Src or ERK signaling-mediated cell proliferation, migration, invasion, and adhesion in various cancer cells [17C20]. The transcription factor signal transducer and activator of transcription 3 (STAT3) is well known to play crucial roles in immunosuppression and tumorigenesis [21C25]. STAT3 is activated by SJFα diverse growth factors, hormones, and cytokines. After phosphorylation of Tyr705, STAT3 forms a dimer and translocates to the nucleus, where it acts as a transcription factor [26]. Tyr705 phosphorylation of STAT3 is mediated by tyrosine kinases such as EGFR [27], JAK [28], and c-Src [29] and activation of downstream signaling results in cell proliferation, migration, and invasion [30]. Nuclear STAT3 binds to the consensus sequences of promoter regions of target genes such as c-Fos, HIF-1, c-Myc, Twist, and survivin, thereby driving their transcription [30C35]. STAT3 can also be phosphorylated at Ser727 by extracellular signal-regulated kinase (ERK), which augments the effect of Tyr705 phosphorylation [36]. However, the precise role of Ser727-phosphorylated STAT3 remains controversial. Survivin is a 16.5 kDa protein that is classified as a member of the inhibitor of apoptosis protein (IAP) family of anti-apoptotic proteins [37]. Survivin can bind caspase-3, Rabbit Polyclonal to OR2D3 a protease effector of cell death, thereby inhibiting its activity [38]. Survivin SJFα has been shown to be abundantly expressed in many human cancers [37], and its expression is increased by many transcription factors, including Sp1 [39], HIF-1 [40], Egr-1 [41], and STAT3 [35]. We found that galectin-1 drives doxorubicin resistance via direct interaction with integrin 1, which in turn activates FAK/c-Src/ERK/STAT3 signaling. This phenomenon culminates in nuclear translocation of STAT3, a transcription factor driving survivin expression, in triple-negative breast cancer cells. RESULTS Galectin-1 is overexpressed in patients with triple negative breast cancer and ablation of galectin-1 decreases secretion and.