Document Type
Dissertation - Open Access
Award Date
2023
Degree Name
Doctor of Philosophy (PhD)
Department / School
Chemistry and Biochemistry
First Advisor
Rachel Willand-Charnley
Abstract
The complex nature of the biology of cancer is still an unraveling science, yielding several biomarkers that have served as molecular targets for detection and treatment of the disease. How sugars, glycans, play a role has remained relatively uninvestigated. Sialic acid (Sia), a sugar residue on the surface of cells, has been identified as a hallmark of cancer and its progression. Sialic acid can be highly functionalized, but we became interested in acetylated Sias. This functional group is modulated by Sialate O- acetylesterase (encoded by the gene SIAE) and Sialate O-acetyltransferase (encoded by CASD1), enzymes that play a crucial role in functionalizing sialic acid. CASD1 and SIAE catalyze the addition and removal of acetyl groups to sialic acids respectively. We showed that modulating SIAE and CASD1 interferes with ligand-receptor binding interactions with adjacent cell surfaces, specifically, we demonstrated that deacetylated Sias reduce NK-mediated cytotoxicity of colon and lung cancer cells via Siglec binding. Building upon this study we turned our attention to understanding how these genes modulate the cell’s susceptibility to drugs. Our findings show that targeting SIAE and CASD1 in chemotherapy renders it more susceptible to drugs that target and inhibit tumor cell proliferation via EGFR signaling. The tested novel hybrid analogs (MMA 294, 320 and 321) and Sorafenib exhibited a dose dependent cytotoxicity via apoptosis on colon and lung cancer cells. The effect of these drugs on the cell cycle of HCT116 and A549 cells was also assessed using DNA staining with propidium iodide. MMA 321 and sorafenib elicited a G0/G1 cell cycle arrest in HCT116 and A549 WT cells but a G2/M in HCT116 and A549 SIAE. Further screening of phosphorylated EGFR by immunofluorescence revealed an overexpression of pEGFR in the CASD1 and SIAE knockout cells suggesting an increased activation of this growth receptor rendering these CRISPR Cas-9 knockout cells highly proliferative but extremely sensitive to the novel hybrid analogs of estrone origin.
Library of Congress Subject Headings
Sialic acids.
Protein-tyrosine kinase -- Inhibitors -- Therapeutic use.
Cancer -- Chemotherapy.
Cell-mediated cytotoxicity.
Drug targeting.
Number of Pages
122
Publisher
South Dakota State University
Recommended Citation
Anim, Mathias Tawiah, "Modulatory Effects of Deacetylated Sialic Acids (a Sugar Residue) in NK-Mediated Cytotoxicity and Targeted Therapy by Receptor Tyrosine Kinase Inhibitors" (2023). Electronic Theses and Dissertations. 493.
https://openprairie.sdstate.edu/etd2/493
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