Date of Award
Bachelor of Science
JoEllen Welsh, Ph.D.
Carmen J. Narvaez, Ph.D
Triple-negative breast cancers (TNBC) are the most aggressive subtype of breast cancer with few treatment options and poor outcomes. TNBCs are characterized by elevations in hexosamine biosynthetic pathway (HBP) enzyme expression, hyaluronan synthase 2 (HAS2) expression and hyaluronan (HA) production. Glutamine is an important substrate for HA production via the HBP. 6-diazo-5-oxo-L-norleucine (DON) is a well-known glutamine antagonist with validated antitumoral efficacy. This project examined the effects of DON on HA production and energy metabolism in TNBC cells. We examined the effect of DON treatment on Hs578T cells, which represent the mesenchymal stem-like subtype of TNBC. We specifically analyzed the effects of DON on Hs578T cell variants segregated into high (HAHigh) and low (HALow) HA producing subpopulations. DON decreased cell proliferation in both cell lines with HALow cells showing a more pronounced effect with almost 40% decrease in cell number after treatment with 2.5μM DON for 72 hours. DON reduced cell-associated HA in a dose dependent manner in HAHigh cells whereas HALow cells exhibited no effect. Seahorse extracellular flux analysis indicated that HAHigh cells were more sensitive to DON with about 60% decrease in glycolysis compared to an almost 40% decrease in HALow cells. The observed changes in glycolysis and reduction in HA production in HAHigh cells support the findings that DON can inhibit glutamine dependent enzymes in HBP and hinder tumor growth in TNBC cells.
Pham, Le Gia Cat, "Glutamine Antagonist 6-diazo-5-oxo-L-norleucine, a Hyaluronan Synthesis Inhibitor, Slows Triple Negative Breast Cancer Growth" (2020). Biological Sciences. 67.