Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging

Tee, Sui Seng, Kim, Nathaniel, Cullen, Quinlan, Eskandari, Roozbeh, Mamakhanyan, Arsen, Srouji, Rami M, Chirayil, Rachel, Jeong, Sangmoo, Shakiba, Mojdeh, Kastenhuber, Edward R, Chen, Shuibing, Sigel, Carlie, Lowe, Scott W, Jarnagin, William R, Thompson, Craig B, Schietinger, Andrea, Keshari, Kayvan R (April 2022) Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging. Science Advances, 8 (14). eabm7985. ISSN 2375-2548

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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 [2-13C]-fructose and dissolving in D2O increased its spin-lattice relaxation time (T1) 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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders Investigative techniques and equipment Investigative techniques and equipment > imaging organs, tissues, organelles, cell types and functions > organs types and functions > liver diseases & disorders > cancer > cancer types > liver cancer organs, tissues, organelles, cell types and functions > organs types and functions organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types
CSHL Authors:	Lowe, Scott W.
Communities:	CSHL labs > Lowe lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	8 April 2022
Date Deposited:	18 Apr 2022 18:49
Last Modified:	17 Jan 2024 15:45
PMCID:	PMC8985914
URI:	https://repository.cshl.edu/id/eprint/40586

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