Interaction of colon cancer cells with glycoconjugates triggers complex changes in gene expression, glucose transporters and cell invasion
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Romana Křivohlavá1, Valika Grobárová1, Eva Neuhöferová1
1Laboratory of Molecular Biology and Immunology, Department of Immunology, Institute of Microbiology, Czech Academy of Sciences, 14220 Prague 4, Czech Republic.
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 N‑acetyl‑D‑glucosamine modified polyamidoamine dendrimer and calix[4]arene scaffold on cancer cell proliferation, apoptosis, invasion and sensitivity to immune cell‑mediated killing. Using reverse transcription‑quantitative 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]arene‑based GC reduced cell colony formation; this was accompanied by the downregulation of the metalloproteinase Mmp3. By contrast, the dendrimer‑based 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 N‑acetyl‑D‑glucosamine‑dendrimer/calix[4]arene GCs alter mRNA expression in a comprehensive way, resulting in the reduced malignant phenotype of the colon cancer cell line HT‑29.
Insights
Synthetic glycoconjugates (GCs) targeting N-acetyl-D-glucosamine show promise in cancer therapy. These GCs reduce colon cancer cell survival and malignant characteristics by altering gene expression, offering a potential new avenue for glycotherapy.
Area of Science:
- Biochemistry and Molecular Biology
- Cancer Research
- Drug Discovery
Background:
- Glycan metabolism and glycosylation are crucial for cellular functions, including communication, signaling, and survival.
- Aberrant glycosylation is a hallmark of cancer, making glycotherapy a potential therapeutic strategy.
- Synthetic glycoconjugates (GCs) offer a novel approach to modulate cellular glycosylation for therapeutic benefit.
Purpose of the Study:
- To investigate the effects of combined synthetic N-acetyl-D-glucosamine modified polyamidoamine dendrimer and calix[4]arene scaffold glycoconjugates (GCs) on colon cancer cell gene expression and malignant phenotype.
- To evaluate the impact of these GCs on colon cancer cell proliferation, apoptosis, invasion, and sensitivity to immune-mediated killing.
Main Methods:
- Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was employed to measure the expression of key genes.
- The study assessed the effects of specific GCs on colon cancer cell line HT-29.
- Analysis included genes involved in glycosylation (Mgat3, Mgat5), Wnt signaling (Wnt2B, Wnt9B), matrix metalloproteinases (Mmp3), glucose transport (Sglt1), and growth factor receptors (Egfr1).
Main Results:
- GCs significantly reduced the expression of Mgat3 and Mgat5, enzymes critical for surface glycosylation.
- Wnt signaling pathway components Wnt2B and Wnt9B expression were decreased by the GCs.
- The calix[4]arene-based GC inhibited colony formation and downregulated Mmp3, while the dendrimer-based GC modulated Sglt1 and Egfr1 expression.
- These comprehensive alterations in mRNA expression led to a reduced malignant phenotype in HT-29 colon cancer cells.
Conclusions:
- N-acetyl-D-glucosamine-based dendrimer and calix[4]arene GCs represent a novel therapeutic strategy for colon cancer.
- These GCs effectively alter gene expression profiles associated with cancer malignancy.
- The findings provide the first evidence of GCs comprehensively reducing the malignant phenotype of the HT-29 colon cancer cell line, supporting their potential in glycotherapy.
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