Ketohexokinase-mediated Fructose Metabolism is Lost in Hepatocellular Carcinoma and Can Be Leveraged for Metabolic Imaging

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2022 Apr 6

PMID 35385296

Authors

Sui Seng Tee

Nathaniel Kim

Quinlan Cullen

Roozbeh Eskandari

Arsen Mamakhanyan

Rami M Srouji

Rachel Chirayil

Sangmoo Jeong

Mojdeh Shakiba

Edward R Kastenhuber

Shuibing Chen

Carlie Sigel

Scott W Lowe

William R Jarnagin

Craig B Thompson

Andrea Schietinger

Kayvan R Keshari

Affiliations

Soon will be listed here.

Abstract

The ability to break down fructose is dependent on ketohexokinase (KHK) that phosphorylates fructose to fructose-1-phosphate (F1P). We show that KHK expression is tightly controlled and limited to a small number of organs and is down-regulated in liver and intestinal cancer cells. Loss of fructose metabolism is also apparent in hepatocellular adenoma and carcinoma (HCC) patient samples. KHK overexpression in liver cancer cells results in decreased fructose flux through glycolysis. We then developed a strategy to detect this metabolic switch in vivo using hyperpolarized magnetic resonance spectroscopy. Uniformly deuterating [2-C]-fructose and dissolving in DO increased its spin-lattice relaxation time () fivefold, enabling detection of F1P and its loss in models of HCC. In summary, we posit that in the liver, fructolysis to F1P is lost in the development of cancer and can be used as a biomarker of tissue function in the clinic using metabolic imaging.

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