Binding of galectin-1 to integrin β1 potentiates drug resistance by promoting survivin expression in breast cancer cells

Abstract

Galectin-1 is a β-galactoside binding protein secreted by many types of aggressive cancer cells. Although many studies have focused on the role of galectin-1 in cancer progression, relatively little attention has been paid to galectin-1 as an extracellular therapeutic target. To elucidate the molecular mechanisms underlying galectin-1-mediated cancer progression, we established galectin-1 knock-down cells via retroviral delivery of short hairpin RNA (shRNA) against galectin-1 in two triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and Hs578T. Ablation of galectin-1 expression decreased cell proliferation, migration, invasion, and doxorubicin resistance. We found that these effects were caused by decreased galectin-1-integrin β1 interactions and suppression of the downstream focal adhesion kinase (FAK)/c-Src pathway. We also found that silencing of galectin-1 inhibited extracellular signal-regulated kinase (ERK)/signal transducer and activator of transcription 3 (STAT3) signaling, thereby down-regulating survivin expression. This finding implicates STAT3 as a transcription factor for survivin. Finally, rescue of endogenous galectin-1 knock-down and recombinant galectin-1 treatment both recovered signaling through the FAK/c-Src/ERK/STAT3/survivin pathway. Taken together, these results suggest that extracellular galectin-1 contributes to cancer progression and doxorubicin resistance in TNBC cells. These effects appear to be mediated by galectin-1-induced up-regulation of the integrin β1/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.

Response prediction to oxaliplatin plus 5‑fluorouracil chemotherapy in patients with colorectal cancer using a four‑protein immunohistochemical model

“…Based on this evidence, the present study established a predictive model of α-SMA, p-AKT, p-ERK and survivin expression in patients with CRC in order to anticipate the potential intrinsic resistance to the oxaliplatin plus 5-FU regimen. The results from this study demonstrated that α-SMA and survivin overexpression in patients with CRC was significantly associated with oxaliplatin plus 5-FU resistance, which was not the case for p-AKT and p-ERK overexpression; this result was in agreement with previous studies and hypotheses (19,(43)(44)(45). From these different patterns, the model comprising α-SMA, p-AKT, p-ERK and survivin overexpression was the best predictive pattern.…”

“…Survivin is a member of the inhibitor of apoptosis proteins family. Numerous studies have demonstrated that survivin overexpression is associated with drug resistance in different cancer types (19,(38)(39)(40). The potential mechanisms involved in survivin overexpression-induced drug resistance are as follows: i) Nuclear survivin serves a pivotal role in the formation of spindle fiber assembly via stabilization of microtubule formation leading to cell growth (41); ii) survivin can upregulate the molecular sensor of DNA damage named ku70 and subsequently enhance the repair of DNA double-stranded breaks (42); and iii) survivin can interact with the apoptosis-inducing molecules caspase-3 and casapase-9 and inhibit their apoptotic function (43).…”

“…In addition, it has been reported that the MAPK (12)(13)(14) and PI3K/AKT/mTOR (15)(16)(17)(18) pathways serve key roles in drug resistance, notably in CRC, and that PI3K/AKT signaling pathway inhibition can reduce resistance to chemotherapeutic drugs. It was also reported that survivin overexpression, which may be a downstream effect of the MAPK or PI3K-AKT-mTOR signaling pathway (19), is associated with drug resistance in CRC. As all these findings focus on cellular and molecular approaches, it is essential to verify whether they exist in patients with CRC.…”

Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus-1 with Integrin β1 Blocking Antibody OS2966

“…Apart from direct tumor cell and ECM interactions, integrins are also known to engage in crosstalk with growth factor receptors, such as EGFR, in the cell-cycle progression in cancer cells. Several studies have implicated that integrin b1 functions during origination, growth, progression, and therapeutic resistance of solid tumors, including GBM and breast cancer with brain metastasis, by promoting stromal and growth factor derived oncogenic signaling (37,38). More recently, downregulation of integrin b1 inhibited mesenchymal function in resistant GBM cells and decreased phosphorylations of EGFR and c-Met in hepatocytes during liver regeneration (6,7,39).…”

Comprehensive network analysis of integrin α11 expressed in human breast cancer

“…The GO terminology for the GO enrichment analysis and EC analysis was retrieved from DAVID (http://david.abcc.ncifcrf.gov/). For the GO enrichment analysis, the significant difference of GO enrichment in co-expressed genes was evaluated against a background set consisting of 15,438 genes, at least one of which was derived from a human co-expressed network dataset using hypergeometric distribution. Without multiple test correlations, the BP p-value <0.01 and MF p-value <0.1 were set as significance thresholds.…”