DOI
https://doi.org/10.25772/282X-FN81
Defense Date
2025
Document Type
Thesis
Degree Name
Master of Science
Department
Biology
First Advisor
Santiago Lima
Abstract
Multidrug resistance (MDR) remains a major obstacle in cancer therapy, contributing to nearly 90% of cancer-related deaths. While ceramides and their downstream metabolites have been extensively studied in relation to chemoresistance, the role of upstream precursors and key enzymes in ceramide metabolism remains less understood. This study explores two objectives: whether the fatty acyl-CoA precursors 16:0 CoA and 24:0 CoA influence chemoresistance in lung epithelial cell models, and whether the enzyme glucosylceramidase beta (GBA), which hydrolyzes glucosylceramide (GlcCer) into ceramide, modulates the expression of MDR-associated transporters and alters drug response across cancer cell lines. In Chapter 1, HBEC-derived lung epithelial lines with distinct resistance profiles were treated with 16:0 and 24:0 CoA to assess changes in growth, viability, lipid composition, invasion potential, and drug sensitivity. Lipidomic analysis confirmed precursor incorporation into ceramide species. 16:0 CoA promoted resistance in p53-deficient cells but decreased viability in others, while 24:0 CoA unexpectedly increased chemosensitivity in specific contexts. Chapter 2 evaluated GBA’s role across cancer models, showing that GBA knockdown reduced MDR1 and MRP1 expression and sensitized H1299 cells to vinorelbine and paclitaxel, but in H460 cells, knockdown increased transporter expression and chemoresistance, suggesting cell-type-dependent effects. These differences may reflect variations in lipid metabolism, stress responses, or oncogenic signaling. Overall, this study reveals that fatty acyl-CoA precursors and GBA expression significantly influence chemoresistance in a context-specific manner, linking ceramide metabolism to ABC transporter regulation and offering insights for developing targeted strategies against resistant cancers.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-12-2025