Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Celeste Simon

Abstract

Deregulated glucose metabolism is a critical component of cancer growth and survival, as is clinically evident by FDG-PET imaging of enhanced glucose uptake in tumors. However, the efficacy of direct pharmacological intervention of glycolysis, a critical biochemical pathway that catabolizes glucose, has yet to be realized. As an alternative approach, we explored the potential therapeutic value of two physiological pathways that oppose glucose catabolism in either liver or kidney cancer: gluconeogenesis and glycogen synthesis, respectively. In liver cancer, I hypothesized that gluconeogenesis could be stimulated by glucagon signaling to antagonize glycolysis and reduce tumor cell growth. Upon supraphysiologic overexpression of the glucagon receptor, GCGR, glucagon treatment of the liver cancer cell line, SNU398, reproducibly decreased cell viability, but without transcriptionally inducing gluconeogenic gene expression, regardless of the epigenetic landscape. In kidney cancer, we hypothesized that disrupting glycogen breakdown could prevent release of glucose under stress conditions and inhibit tumor cell proliferation. Through genetic knockout of key enzymes and carbon-13 labeling, we observed that glycogen metabolism does not affect tumor growth, despite metabolic utilization of glycogen-derived glucose in culture conditions without glucose. In conclusion, we describe context-specific approaches to targeting glucose metabolism in cancer that warrant further investigation.

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