Advisory Committee Chair
Susan L Bellis
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
An emerging concept in cancer biology is that surface glycosylation can play important roles in the regulation of cancer development and progression. Our group and others have shown that ST6Gal-I, a sialyltransferase that adds α2-6-linked sialic acids to N-glycosylated proteins, is upregulated in many cancers. Furthermore, data has indicated that ST6Gal-I acts as a pro-survival factor in a variety of settings, including resistance to chemotherapeutic drugs, radiotherapy resistance, and serum deprivation. The work presented in this dissertation adds to this understanding of ST6Gal-I’s role as a potent pro-survival factor and explores ST6Gal-I’s function in aiding tumor cells to survive hypoxic stress. When subjected to hypoxic stress, ST6Gal-I expressing cells have increased accumulation of the master regulator of the cellular response to hypoxia, HIF-1α. This increased accumulation was accompanied by increased transcription of HIF-1α target genes associated with glycolysis and angiogenesis. Given this data, the metabolism of ST6Gal-I expressing cells was assessed using Seahorse technology. We found that cells with high expression of ST6Gal-I had higher rates of both oxidative phosphorylation and glycolysis. However, the increased oxidative phosphorylation rate was not accompanied by increased mitochondria number. Additionally, we found that when we treat with the hypoxia mimetic, DFO, cells with forced expression of ST6Gal-I were able to maintain higher metabolic rates overall. These data indicate that cells with high expression of ST6Gal-I are better able to adapt to hypoxic stress by altering their metabolic rates. We further demonstrate that high expression of ST6Gal-I leads to increased glycolysis in normoxia consistent with Warburg effect. This increased glycolytic rate was accompanied by increased activity of the rate limiting glycolytic enzymes hexokinase and phosphofructokinase. Taken together, these data highlight a novel glycosylation dependent mechanism for the regulation of tumor metabolism.
Jones, Robert Brent, "The Role Of The St6Gal-I Sialyltrasferase In Protecting Tumor Cells From Hypoxic Stress" (2019). All ETDs from UAB. 2071.