ABSTRACT
Glycan metabolism balance is critical for cell prosperity, and macromolecule glycosylation is essential for cell communication, signaling and survival. Thus, glycotherapy may be a potential cancer treatment. The aim of the present study was to determine whether combined synthetic glycoconjugates (GCs) induce changes in gene expression that alter the survival of colon cancer cells. The current study evaluated the effect of the GCs NacetylDglucosamine modified polyamidoamine dendrimer and calix[4]arene scaffold on cancer cell proliferation, apoptosis, invasion and sensitivity to immune cellmediated killing. Using reverse transcriptionquantitative polymerase chain reaction, the expression of genes involved in the aforementioned processes was measured. It was determined that GCs reduce the expression of the glucosaminyltransferases Mgat3 and Mgat5 responsible for surface glycosylation and employed components of the Wnt signaling pathway Wnt2B and Wnt9B. In addition, the calix[4]arenebased GC reduced cell colony formation; this was accompanied by the downregulation of the metalloproteinase Mmp3. By contrast, the dendrimerbased GC affected the expression of the glucose transporter components Sglt1 and Egfr1. Therefore, to the best of our knowledge, the present study is the first to reveal that NacetylDglucosaminedendrimer/calix[4]arene GCs alter mRNA expression in a comprehensive way, resulting in the reduced malignant phenotype of the colon cancer cell line HT29.
Subject(s)
Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Glucose Transport Proteins, Facilitative/genetics , Glycoconjugates/pharmacology , Apoptosis/genetics , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Cell Line, Tumor , Cell Proliferation , Cell Survival/drug effects , Gene Expression Profiling , Glucose/metabolism , HT29 Cells , Humans , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Transcriptome , Tumor Stem Cell AssayABSTRACT
Aberrant glycosylation, which impairs recognition capability of NK cells or modifies recognition pattern of target cells, is associated with cancer. Synthetic glycoconjugates (GCs), which modulate cell glycosylation, increase the sensitivity of tumor cells to therapy or boost anti-cancer immune response. In the current study, we employed N-acetyl-D-glucosamine-calix[4]arene (GN4C) as a modulator of cell glycosylation of NK cells represented by the NK-92 cell line and fresh human NK cells. For the first time, we have demonstrated that calix[4]arene-based GC down-regulated the expression of glycosyltransferases MGAT3 and MGAT5 in NK-92 and fresh NK cells. GN4C increased the susceptibility of tumor cells to cytotoxicity by purified fresh NK cells or NK-92 cells. This functional activation of NK cells and the NK-92 cell line correlated with an increased expression of NKG2D mRNA. In the NK-92 cell line, GN4C induced the synthesis of IL-2, IFN-gamma and tumor necrosis factor-alpha as well. Cellular signaling triggered by GN4C engaged PI3-kinase/ERK but not phospholipase C-gamma/JNK pathways. Simultaneously, in transformed NK-92 cells, GN4C reduced the rate of proliferation and down-regulated the c-MYC, EGF-receptor 1 and REL-A molecules. In conclusion, the modulation of glycosyltransferases MGAT3 and MGAT5 by synthetic GN4C correlated with the improvement of NK cell effector functions and the augmentation of tumor cells sensitivity to NK cell-mediated cytotoxicity.