Date of Award

Winter 12-15-2022

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Biochemistry)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

The amount of dietary fructose consumed in the United States has increased considerably over the past five decades, largely due to the widespread use of high fructose corn syrup as a sweetener. The potential link between this elevated fructose intake and the development of cancer remains incompletely understood. Here we show that, even though cervical cancer cells themselves cannot directly utilize fructose carbon, diets high in fructose enhance the growth of cervical tumors by nearly threefold in mice. We demonstrate that efficient utilization of fructose carbon requires ketohexokinase-C, which was not expressed in ~100 cervical tumors that we examined from human patients or any transformed cancer cell line that we studied in vitro. In contrast, primary hepatocytes did express ketohexokinase-C. In a co-culture system, primary hepatocytes fed cervical cancer cells fructose-derived nutrients that drove proliferation of cancer cells through metabolite exchange. Similarly, in mice bearing cervical tumors, metabolism of fructose in ketohexokinase-C-expressing tissues enhanced tumor growth through a cell non-autonomous mechanism. We demonstrate that PF-06835919, a drug in clinical trials to inhibit ketohexokinase-C in non-alcoholic fatty liver disease, had no direct effects on cervical cancer cells themselves. Yet, when given to mice with cervical cancer, it was sufficient to prevent diets high in fructose from promoting tumor growth by inhibiting ketohexokinase-C in non-malignant tissue. These findings suggest that PF-06835919 has anti-tumor activity and demonstrate a therapeutic paradigm where non-malignant, distal organs may be targeted as a treatment for cancer.

Language

English (en)

Chair and Committee

Gary Patti

Committee Members

Brian Finck

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